## Simulations

##### Data classification:Simulations: The datasets produced as a result of applying the models to different scientific techniques.Proteins: The biological proteins associated with the SARS-CoV-2 virus and host.Structures: Data defining structures determined by experimental methods and referenced via a unique identifier such as a PDB ID.Models: Derived, integrated, or refined structures from multiple data sources prepared for different computational tasks.
• Unpublished data with no preprints have no indicator
• Data in a preprint or submitted for publication are given this marker. If the preprint is available, it will always show and should work as a link
• Data published in a paper or accepted are given this marker (i.e. has been approved by formal peer review) and should work as links.

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## Simulations of Viral Spike Proteins

### Blocking SARS-CoV-2 Spike protein binding to human ACE2 receptor

#### DESRES-ANTON-11021566 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein in aqueous solution (10 µs )

##### 10 µs simulation trajectory of the trimeric SARS-CoV-2 spike glycoprotein with additional loop structures and glycan chains to improve the spike protein model originally released in DESRES-ANTON-[10897136,10897850]. Trajectory was initiated in the closed state (PDB entry 6VXX). The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10897136 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein in aqueous solution (10 µs )

##### A 10 µs simulation of the trimeric SARS-CoV-2 spike glycoprotein. System was initiated in the closed state (PDB entry 6VXX), which remained stable. The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The total number of atoms in the system was 566502 for the closed state. The interval between frames is 1.2 ns. The simulation was conducted at 310 K in the NPT ensemble. We have released new versions of these simulations with enhancements to the spike protein model in [DESRES-ANTON-11021566,11021571] (https://www.deshawresearch.com/downloads/download_trajectory_sarscov2.cgi/#DESRES-ANTON-11021566), since the one used in this simulation is incomplete in some of the disordered loop regions (i.e., resid 455 to 461, resid 469 to 488) and in glycan chains.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10897850 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein in aqueous solution (10 µs )

##### A 10 µs simulation of the trimeric SARS-CoV-2 spike glycoprotein. System was initiated in a partially opened state (PDB entry 6VYB) which exhibited a high degree of conformational heterogeneity. In particular, the partially detached receptor binding domain sampled a variety of orientations, and further detached from the S2 fusion machinery. The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The total number of atoms in the system was 715439 for the closed state. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble. We have released new versions of these simulations with enhancements to the spike protein model in [DESRES-ANTON-11021566,11021571] (https://www.deshawresearch.com/downloads/download_trajectory_sarscov2.cgi/#DESRES-ANTON-11021566), since the one used in this simulation is incomplete in some of the disordered loop regions (i.e., resid 455 to 461, resid 469 to 488) and in glycan chains.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10897850 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein, no water or ions (10 µs )

##### A 10 µs simulation of the trimeric SARS-CoV-2 spike glycoprotein. System was initiated in a partially opened state (PDB entry 6VYB) which exhibited a high degree of conformational heterogeneity. In particular, the partially detached receptor binding domain sampled a variety of orientations, and further detached from the S2 fusion machinery. The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The total number of atoms in the system was 715439 for the closed state. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble. We have released new versions of these simulations with enhancements to the spike protein model in [DESRES-ANTON-11021566,11021571] (https://www.deshawresearch.com/downloads/download_trajectory_sarscov2.cgi/#DESRES-ANTON-11021566), since the one used in this simulation is incomplete in some of the disordered loop regions (i.e., resid 455 to 461, resid 469 to 488) and in glycan chains.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10906555 2 µs simulations of 50 FDA approved or investigational drug molecules binding to a construct of the SARS-CoV-2 trimeric spike protein, no water or ions (2 µs )

##### 50 2 µs trajectories of FDA approved or investigational drug molecules that in simulation remained bound to a construct of the SARS-CoV-2 trimeric spike protein at positions that might conceivably allosterically disrupt the interaction between these proteins. The small molecule drugs and their initial binding poses were chosen from a combination of molecular dynamics simulation and docking performed using an FDA-investigational drug library. The 50 putative spike protein binding small molecules located at three regions on the spike trimer, a pocket in the RBD whose formation may possibly enhance RBD-RBD interactions in the closed conformation (8 molecules), a pocket between the two RBDs in the closed conformation (29 molecules), and a pocket that involves three RBDs in the closed conformation (13 molecules). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for small molecules. The C- and N-peptide termini were capped with amide and acetyl groups respectively. The spike trimer construct was modeled from PDB entries 6VXX and 6VW1, only retaining the RBD and a short region from S1 fusion protein as a minimal system for maintaining a trimer assembly. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10906555 2 µs simulations of 50 FDA approved or investigational drug molecules binding to a construct of the SARS-CoV-2 trimeric spike protein (2 µs )

##### 50 2 µs trajectories of FDA approved or investigational drug molecules that in simulation remained bound to a construct of the SARS-CoV-2 trimeric spike protein at positions that might conceivably allosterically disrupt the interaction between these proteins. The small molecule drugs and their initial binding poses were chosen from a combination of molecular dynamics simulation and docking performed using an FDA-investigational drug library. The 50 putative spike protein binding small molecules located at three regions on the spike trimer, a pocket in the RBD whose formation may possibly enhance RBD-RBD interactions in the closed conformation (8 molecules), a pocket between the two RBDs in the closed conformation (29 molecules), and a pocket that involves three RBDs in the closed conformation (13 molecules). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for small molecules. The C- and N-peptide termini were capped with amide and acetyl groups respectively. The spike trimer construct was modeled from PDB entries 6VXX and 6VW1, only retaining the RBD and a short region from S1 fusion protein as a minimal system for maintaining a trimer assembly. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10897136 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein, no water or ions (10 µs )

##### A 10 µs simulation of the trimeric SARS-CoV-2 spike glycoprotein. System was initiated in the closed state (PDB entry 6VXX), which remained stable. The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The total number of atoms in the system was 566502 for the closed state. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble. We have released new versions of these simulations with enhancements to the spike protein model in [DESRES-ANTON-11021566,11021571] (https://www.deshawresearch.com/downloads/download_trajectory_sarscov2.cgi/#DESRES-ANTON-11021566), since the one used in this simulation is incomplete in some of the disordered loop regions (i.e., resid 455 to 461, resid 469 to 488) and in glycan chains.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-11021571 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein in aqueous solution (10 µs )

##### 10 µs simulation trajectory of the trimeric SARS-CoV-2 spike glycoprotein with additional loop structures and glycan chains to improve the spike protein model originally released in DESRES-ANTON-[10897136,10897850]. Trajectory was initiated in a partially opened state (PDB entry 6VYB). The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-11021566 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein, no water or ions (10 µs )

##### 10 µs simulation trajectory of the trimeric SARS-CoV-2 spike glycoprotein with additional loop structures and glycan chains to improve the spike protein model originally released in DESRES-ANTON-[10897136,10897850]. Trajectory was initiated in the closed state (PDB entry 6VXX). The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-11021571 10 µs simulation of of the trimeric SARS-CoV-2 spike glycoprotein, no water or ions (10 µs )

##### 10 µs simulation trajectory of the trimeric SARS-CoV-2 spike glycoprotein with additional loop structures and glycan chains to improve the spike protein model originally released in DESRES-ANTON-[10897136,10897850]. Trajectory was initiated in a partially opened state (PDB entry 6VYB). The simulation used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and N-peptide termini are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

### No Targets Recorded

#### Gromacs 60 ns MD of SARS-CoV-2 spike trimer, All Atom model (60 ns )

##### This trajectory is from a 60 ns MD simulation of the SARS-CoV-2 spike protein. The protein was solvated in a 20 x 20 x 20 nm water box containing 0.1 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Charmm27 force field. The interval between frames is 80 ps. The simulation was conducted in the NPT ensemble (1 bar). This trajectory is all atom.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.1Charmm27

#### Trajectories of full-length SPIKE protein in the Closed state. (1.7 µs )

##### All-atom MD simulations of full-length SPIKE protein in the Closed state, protein + glycans only (not aligned). PSF and DCDs files are provided.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15CHARMM36
TIP3P

#### Trajectories of full-length SPIKE protein in the Open state. (4.2 µs )

##### All-atom MD simulations of full-length SPIKE protein in the Open state, protein + glycans only (not aligned). PSF and DCDs files are provided.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15CHARMM36
TIP3P

#### Trajectories of full-length SPIKE protein in the Open state (N165A / N234A mutations). (4.2 µs )

##### All-atom MD simulations of full-length SPIKE protein in the Open state bearing N165A and N234A mutations, protein + glycans only (not aligned). PSF and DCDs files are provided.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15CHARMM36
TIP3P

## Simulations of Viral Protease, Polymerase, and Nonstructured Proteins

### 3CLpro / Mpro activity

#### DESRES 100 µs MD of 3CLpro, no water or ions (100 µs )

##### This trajectory is from a 100 µs MD simulation of the apo enzyme started from the apo enzyme structure determined by X-ray crystallography (PDB entry 6Y84) The protein was solvated in a 120 x 120 x 120 Å water box containing 0.15 M NaCl. The simulation was performed on Anton 2 using the DES-Amber force field The interval between frames is 1 ns. The simulation was conducted in the NPT ensemble. This trajectory has been stripped of all waters and ions
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT2981Water0.15DES-Amber FF

#### HADDOCK docking of approved Drugbank set against Mpro with a geometric shape model

##### Repurposing study of the approved subset of Drugbank + active metabolites + investigational compounds of interest against Mpro. Compounds are guided to the binding site using 3D shape data extracted from a plethora of templates available on the PDB and also through the Diamond assay. The template compound shapes have been superimposed on the binding pocket of 6Y2F which is the receptor that was used for the docking. Ambiguous distance restraints are defined between target compound atoms and the template shape beads. Docking is performed in vacuum using the OPLS (UA) forcefield with a shifting function and a target of 8.5Å for the electrostatic energy and a switching function between 6.5 and 8.5Å for vdW energy, respectively. Compounds are scored using a scoring function comprised of the sum of vdW and electrostatics energies and an empirical desolvation potential.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
DockingOtherN/AN/AvacuumN/AOPLS-UA

#### Riken BDR 10 Microsecond Trajectory Protein Snapshot every 1ns (10 µs )

##### Single 10 microseconds trajectory of SARS-CoV-2 dimeric main protease, NVT at 310K, with the time step 2.5fs (more precisely, 2.500000409 fs). The starting structure was prepared based on PDB 6LU7, with amber99sb-ildn force field. The system is composed of 98,694 atoms in 9.98921 nm length cubic box with periodic boundary conditions. Simulation performed in aqueous solution with solvent forcefield TIP3P.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNVT310N/AWaterN/Aamber99sb-ildn
TIP3P

#### Riken BDR 10 Microsecond Trajectory System Snapshot every 10ns (10 µs )

##### Single 10 microseconds trajectory of SARS-CoV-2 dimeric main protease, NVT at 310K, with the time step 2.5fs (more precisely, 2.500000409 fs). The starting structure was prepared based on PDB 6LU7, with amber99sb-ildn force field. The system is composed of 98,694 atoms in 9.98921 nm length cubic box with periodic boundary conditions. Simulation performed in aqueous solution with solvent forcefield TIP3P.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNVT310N/AWaterN/Aamber99sb-ildn
TIP3P

#### Riken BDR 10 Microsecond Trajectory Protein Snapshot every 200ps (10 µs )

##### Single 10 microseconds trajectory of SARS-CoV-2 dimeric main protease, NVT at 310K, with the time step 2.5fs (more precisely, 2.500000409 fs). The starting structure was prepared based on PDB 6LU7, with amber99sb-ildn force field. The system is composed of 98,694 atoms in 9.98921 nm length cubic box with periodic boundary conditions. Simulation performed in aqueous solution with solvent forcefield TIP3P.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNVT310N/AWaterN/Aamber99sb-ildn
TIP3P

#### DESRES 100 µs MD of 3CLpro, All Atom (100 µs )

##### This trajectory is from a 100 µs MD simulation of the apo enzyme started from the apo enzyme structure determined by X-ray crystallography (PDB entry 6Y84) The protein was solvated in a 120 x 120 x 120 Å water box containing 0.15 M NaCl. The simulation was performed on Anton 2 using the DES-Amber force field The interval between frames is 1 ns. The simulation was conducted in the NPT ensemble. This trajectory is all atom
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT2981Water0.15DES-Amber FF

#### HADDOCK docking of approved Drugbank set against Mpro with a pharmacophore shape model

##### Repurposing study of the approved subset of Drugbank + active metabolites + investigational compounds of interest against Mpro. Compounds are guided to the binding site using 3D pharmacophore data extracted from a plethora of templates available on the PDB and also through the Diamond assay. The template compound shapes have been superimposed on the binding pocket of 6Y2F which is the receptor that was used for the docking. Ambiguous distance restraints are defined between target compound atoms and the template shape beads. Docking is performed in vacuum using the OPLS (UA) forcefield with a shifting function and a target of 8.5Å for the electrostatic energy and a switching function between 6.5 and 8.5Å for vdW energy, respectively. Compounds are scored using a scoring function comprised of the sum of vdW and electrostatics energies and an empirical desolvation potential.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
DockingOtherN/AN/AvacuumN/AOPLS-UA

### Inhibition of PLpro protease activity

#### 3k bound SARS-CoV PLPro (1 μs )

##### 1μs MD trajectory generated using Amber, FF14SB force field trajectory, GAFF2 for ligand, AM1-BCC charges for ligand; stripped water molecules and counter ions.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT2980.987WaterN/AFF14SB
GAFF2

#### 3k bound SARS-CoV-2 PLPro (3k docked to frame from trajectory of PDB 6W9C C-chain) (1 μs )

##### 1μs MD trajectory generated using Amber, FF14SB force field trajectory, GAFF2 for ligand, AM1-BCC charges for ligand; stripped water molecules and counter ions.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT2980.987WaterN/AFF14SB
GAFF2

#### Apo SARS-CoV-2 PLPro (from PDB 6WRH C-chain) (1 μs )

##### 1μs MD trajectory generated using Amber, FF14SB force field trajectory, stripped water molecules and counter ions.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT2980.987WaterN/AFF14SB

#### Apo SARS-CoV-2 PLPro (from PDB 6W9C C-chain) (1 μs )

##### 1μs MD trajectory generated using Amber, FF14SB force field trajectory, stripped water molecules and counter ions.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT2980.987WaterN/AFF14SB

#### Apo SARS-CoV PLpro (1 μs )

##### 1μs MD trajectory generated using Amber, FF14SB force field trajectory, stripped of water molecules and counter ions.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT2980.987WaterN/AFF14SB

### Inhibition of viral polymerases

#### Gromacs 100 ns MD of SARS-CoV-2 RdRp + RNA template-primer + ATP model, All Atom model (100 ns )

##### This trajectory is from a 100 ns atomic MD simulation of the SARS-CoV-2 RdRp-RNA-ATP-complex protein. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 100 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### Gromacs 300 ns MD of SARS-CoV-2 apo-RdRp model, All Atom model (300 ns )

##### This trajectory is from a 300 ns atomic MD simulation of the SARS-CoV-2 RdRp apo-protein model. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 400 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### DESRES-ANTON-10917618 10 µs simulation of SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex, no water or zinc (10 µs )

##### A 10 µs simulation trajectory of the SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex determined in the absence of reducing agent (PDB entry 6M71). In the simulation, the partially disordered N-terminal region (residue 30 to residue 120) of the NiRAN domain folded into a stable ordered structure that resembles the N-lobe fold of protein kinases. Lys 73 in β3 forms a salt bridge with Glu 83 in αC for most of the simulation, a common feature of protein kinases. The protein kinase-like fold formed in simulation is in good agreement with the structure of the same complex determined in the presence of reducing agent (PDB entry 7BTF). Structural comparison shows that the protein kinase-like fold in the NiRAN domain shares high similarity with that of the bacterial protein SELO, a protein kinase that catalyzes the transfer of adenosine 5’-monophosphate (AMP) to Ser, Thr and Tyr residues of target proteins, consistent with a potential connection between SELO and SARS-CoV-1 nps12 noted in a previous study. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water. The C- and N-peptide termini capped with amide and acetyl groups respectively. The missing loops in the published structural models were manually built as extended peptide conformation. The missing part of Chain D was built through homology modeling using the structure of SARS-CoV-1 polymerase complex (PDB entry 6NUR). The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted in the NPT ensemble. The structural similarity search was done using the DALI server, and the SELO structure (PDB entry 6EAC) was the highest ranked protein in the list.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P

#### Gromacs 100 ns MD of SARS-CoV-2 RdRp + RNA template-primer + RTP (Remdesivir Tri-Phosphate) model, All Atom model (100 ns )

##### This trajectory is from a 100 ns atomic MD simulation of the SARS-CoV-2 RdRp-RNA-RTP-complex protein. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 100 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### HADDOCK docking of approved Drugbank set against RdRp

##### Repurposing study of the approved subset of Drugbank + active metabolites + investigational compounds of interest against RdRp. Compounds are guided to the binding site using restraints extracted from PDB id 7BV2. The binding sire residues have been defined using a distance cut-off of 5Å. Docking is performed in vacuum using the OPLS (UA) forcefield with a shifting and switching function for vdW and electrostatics energies, respectively. Scaling of intermolecular energies was lowered to 1/1000 of their original values for the initial rigid-body docking stage to allow the compounds to more easily penetrate into the binding pocket. Compounds are scored using a scoring function comprised of the sum of vdW and electrostatics energies and an empirical desolvation potential. respectively.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
DockingOtherN/AN/AvacuumN/AOPLS-UA

#### DESRES-ANTON-10917618 10 µs simulation of SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex in aqueous solution (10 µs )

##### A 10 µs simulation trajectory of the SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex determined in the absence of reducing agent (PDB entry 6M71). In the simulation, the partially disordered N-terminal region (residue 30 to residue 120) of the NiRAN domain folded into a stable ordered structure that resembles the N-lobe fold of protein kinases. Lys 73 in β3 forms a salt bridge with Glu 83 in αC for most of the simulation, a common feature of protein kinases. The protein kinase-like fold formed in simulation is in good agreement with the structure of the same complex determined in the presence of reducing agent (PDB entry 7BTF). Structural comparison shows that the protein kinase-like fold in the NiRAN domain shares high similarity with that of the bacterial protein SELO, a protein kinase that catalyzes the transfer of adenosine 5’-monophosphate (AMP) to Ser, Thr and Tyr residues of target proteins, consistent with a potential connection between SELO and SARS-CoV-1 nps12 noted in a previous study. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water. The C- and N-peptide termini capped with amide and acetyl groups respectively. The missing loops in the published structural models were manually built as extended peptide conformation. The missing part of Chain D was built through homology modeling using the structure of SARS-CoV-1 polymerase complex (PDB entry 6NUR). The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted in the NPT ensemble. The structural similarity search was done using the DALI server, and the SELO structure (PDB entry 6EAC) was the highest ranked protein in the list.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P

### Inhibition of viral polymerases

#### DESRES-ANTON-10917618 10 µs simulation of SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex, no water or zinc (10 µs )

##### A 10 µs simulation trajectory of the SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex determined in the absence of reducing agent (PDB entry 6M71). In the simulation, the partially disordered N-terminal region (residue 30 to residue 120) of the NiRAN domain folded into a stable ordered structure that resembles the N-lobe fold of protein kinases. Lys 73 in β3 forms a salt bridge with Glu 83 in αC for most of the simulation, a common feature of protein kinases. The protein kinase-like fold formed in simulation is in good agreement with the structure of the same complex determined in the presence of reducing agent (PDB entry 7BTF). Structural comparison shows that the protein kinase-like fold in the NiRAN domain shares high similarity with that of the bacterial protein SELO, a protein kinase that catalyzes the transfer of adenosine 5’-monophosphate (AMP) to Ser, Thr and Tyr residues of target proteins, consistent with a potential connection between SELO and SARS-CoV-1 nps12 noted in a previous study. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water. The C- and N-peptide termini capped with amide and acetyl groups respectively. The missing loops in the published structural models were manually built as extended peptide conformation. The missing part of Chain D was built through homology modeling using the structure of SARS-CoV-1 polymerase complex (PDB entry 6NUR). The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted in the NPT ensemble. The structural similarity search was done using the DALI server, and the SELO structure (PDB entry 6EAC) was the highest ranked protein in the list.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P

#### Gromacs 100 ns MD of SARS-CoV-2 RdRp + RNA template-primer + RTP (Remdesivir Tri-Phosphate) model, All Atom model (100 ns )

##### This trajectory is from a 100 ns atomic MD simulation of the SARS-CoV-2 RdRp-RNA-RTP-complex protein. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 100 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### DESRES-ANTON-10917618 10 µs simulation of SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex in aqueous solution (10 µs )

##### A 10 µs simulation trajectory of the SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex determined in the absence of reducing agent (PDB entry 6M71). In the simulation, the partially disordered N-terminal region (residue 30 to residue 120) of the NiRAN domain folded into a stable ordered structure that resembles the N-lobe fold of protein kinases. Lys 73 in β3 forms a salt bridge with Glu 83 in αC for most of the simulation, a common feature of protein kinases. The protein kinase-like fold formed in simulation is in good agreement with the structure of the same complex determined in the presence of reducing agent (PDB entry 7BTF). Structural comparison shows that the protein kinase-like fold in the NiRAN domain shares high similarity with that of the bacterial protein SELO, a protein kinase that catalyzes the transfer of adenosine 5’-monophosphate (AMP) to Ser, Thr and Tyr residues of target proteins, consistent with a potential connection between SELO and SARS-CoV-1 nps12 noted in a previous study. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water. The C- and N-peptide termini capped with amide and acetyl groups respectively. The missing loops in the published structural models were manually built as extended peptide conformation. The missing part of Chain D was built through homology modeling using the structure of SARS-CoV-1 polymerase complex (PDB entry 6NUR). The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted in the NPT ensemble. The structural similarity search was done using the DALI server, and the SELO structure (PDB entry 6EAC) was the highest ranked protein in the list.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P

#### Gromacs 100 ns MD of SARS-CoV-2 RdRp + RNA template-primer + ATP model, All Atom model (100 ns )

##### This trajectory is from a 100 ns atomic MD simulation of the SARS-CoV-2 RdRp-RNA-ATP-complex protein. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 100 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### Gromacs 300 ns MD of SARS-CoV-2 apo-RdRp model, All Atom model (300 ns )

##### This trajectory is from a 300 ns atomic MD simulation of the SARS-CoV-2 RdRp apo-protein model. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 400 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

### Inhibition of viral polymerases

#### Gromacs 100 ns MD of SARS-CoV-2 RdRp + RNA template-primer + ATP model, All Atom model (100 ns )

##### This trajectory is from a 100 ns atomic MD simulation of the SARS-CoV-2 RdRp-RNA-ATP-complex protein. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 100 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### Gromacs 300 ns MD of SARS-CoV-2 apo-RdRp model, All Atom model (300 ns )

##### This trajectory is from a 300 ns atomic MD simulation of the SARS-CoV-2 RdRp apo-protein model. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 400 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### Gromacs 100 ns MD of SARS-CoV-2 RdRp + RNA template-primer + RTP (Remdesivir Tri-Phosphate) model, All Atom model (100 ns )

##### This trajectory is from a 100 ns atomic MD simulation of the SARS-CoV-2 RdRp-RNA-RTP-complex protein. The protein was solvated in a 16 x 16 x 16 nm box of solvent containing water and 0.15 M NaCl. The simulation was performed with Gromacs 2018.8 on the Puhti cluster located at the CSC-IT using the Amber14sb-OL15 force field. The interval between frames is 100 ps. The simulation was conducted in the NPT ensemble (1 bar and 300K).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3000.987Water0.15Amber14sb-OL15

#### DESRES-ANTON-10917618 10 µs simulation of SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex, no water or zinc (10 µs )

##### A 10 µs simulation trajectory of the SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex determined in the absence of reducing agent (PDB entry 6M71). In the simulation, the partially disordered N-terminal region (residue 30 to residue 120) of the NiRAN domain folded into a stable ordered structure that resembles the N-lobe fold of protein kinases. Lys 73 in β3 forms a salt bridge with Glu 83 in αC for most of the simulation, a common feature of protein kinases. The protein kinase-like fold formed in simulation is in good agreement with the structure of the same complex determined in the presence of reducing agent (PDB entry 7BTF). Structural comparison shows that the protein kinase-like fold in the NiRAN domain shares high similarity with that of the bacterial protein SELO, a protein kinase that catalyzes the transfer of adenosine 5’-monophosphate (AMP) to Ser, Thr and Tyr residues of target proteins, consistent with a potential connection between SELO and SARS-CoV-1 nps12 noted in a previous study. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water. The C- and N-peptide termini capped with amide and acetyl groups respectively. The missing loops in the published structural models were manually built as extended peptide conformation. The missing part of Chain D was built through homology modeling using the structure of SARS-CoV-1 polymerase complex (PDB entry 6NUR). The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted in the NPT ensemble. The structural similarity search was done using the DALI server, and the SELO structure (PDB entry 6EAC) was the highest ranked protein in the list.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P

#### DESRES-ANTON-10917618 10 µs simulation of SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex in aqueous solution (10 µs )

##### A 10 µs simulation trajectory of the SARS-CoV-2 nsp7-nsp8-nsp12 RNA polymerase complex determined in the absence of reducing agent (PDB entry 6M71). In the simulation, the partially disordered N-terminal region (residue 30 to residue 120) of the NiRAN domain folded into a stable ordered structure that resembles the N-lobe fold of protein kinases. Lys 73 in β3 forms a salt bridge with Glu 83 in αC for most of the simulation, a common feature of protein kinases. The protein kinase-like fold formed in simulation is in good agreement with the structure of the same complex determined in the presence of reducing agent (PDB entry 7BTF). Structural comparison shows that the protein kinase-like fold in the NiRAN domain shares high similarity with that of the bacterial protein SELO, a protein kinase that catalyzes the transfer of adenosine 5’-monophosphate (AMP) to Ser, Thr and Tyr residues of target proteins, consistent with a potential connection between SELO and SARS-CoV-1 nps12 noted in a previous study. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water. The C- and N-peptide termini capped with amide and acetyl groups respectively. The missing loops in the published structural models were manually built as extended peptide conformation. The missing part of Chain D was built through homology modeling using the structure of SARS-CoV-1 polymerase complex (PDB entry 6NUR). The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted in the NPT ensemble. The structural similarity search was done using the DALI server, and the SELO structure (PDB entry 6EAC) was the highest ranked protein in the list.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P

## Simulations of Host Proteins

### Blocking SARS-CoV-2 Spike protein binding to human ACE2 receptor

#### DESRES-ANTON-10905033 10 µs simulation of the SARS-CoV-2-ACE2 complex, no water or ions (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated from ACE2 in complex with with the receptor binding domain of spike protein SARS-COV-2 (PDB entry 6M17). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### HADDOCK docking of approved Drugbank set against human ACE2 ectodomain

##### Repurposing study of the approved subset of Drugbank + active metabolites + investigational compounds of interest against human ACE2. Compounds are guided to the binding site using restraints extracted from PDB id 1r4l. The binding sire residues have been defined using a distance cut-off of 5Å. Docking is performed in vacuum using the OPLS (UA) forcefield with a shifting and switching function for vdW and electrostatics energies, respectively. Scaling of intermolecular energies was lowered to 1/1000 of their original values for the initial rigid-body docking stage to allow the compounds to more easily penetrate into the binding pocket. Compounds are scored using a scoring function comprised of the sum of vdW and electrostatics energies and an empirical desolvation potential.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
DockingOtherN/AN/AvacuumN/AOPLS-UA

#### DESRES-ANTON-10895671 30 µs of accelerated weighted ensemble MD simulation of a chimeric RBD in complex with ACE2 (30 µs )

##### SARS-CoV-2 attachment to host cells is mediated by a protein-protein interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike and the human ACE2 receptor. We performed a 30 µs of preliminary accelerated weighted ensemble (AWE) MD simulations of a chimeric RBD in complex with ACE2 (PDB entry 6VW1). In the simulation the complex was stable, and no dissociation events were observed. The AWE facilitated sampling of hundreds of binding and thousands of unbinding events over an aggregate 30 µs of AWE simulation. We provide all ~415,000 conformations sampled during the AWE simulations, and the corresponding graph adjacency matrix with weights. From analysis of the AWE simulation data, we also provide four representative trajectories containing binding events and a free energy landscape estimated using a history-augmented Markov state model. The complex model was solvated in a ~140 Å box of 200 mM NaCl and water, and parameterized with the DES-Amber protein and ion force field, the TIP4P-D water model, and an in-house force field derived from GAFF. Simulations were performed under the NPT ensemble at 300 K. During the AWE simulations, we used a 100.8 ps resampling interval to enhance the sampling of (i) the distance between the RBD and ACE2 centers of mass, (ii) the total number of atomic contacts between the RBD and ACE2, and (iii) the complex pRMSD (the square root of the product of the RMSD of the RBD after aligning on ACE2 and the RMSD of ACE2 after aligning on the RBD).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Weighted Ensemble Molecular DynamicsNPT3001water0.2DES-Amber
TIP4P-D
Modified GAFF

#### DESRES-ANTON-10875753 10 µs simulation trajectory of the human ACE2 ectodomain in aqueous solution (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated in an apo open state (PDB entry 1R42). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10875754 10 µs simulation trajectory of the human ACE2 ectodomain, no water or ions (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated in an inhibitor-bound closed state (PDB entry 1R4L). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### A 10 µs simulation of a SARS-CoV-1 and SARS-CoV-2 chimera-ACE2 complex in aqueous solution (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated from ACE2 in complex with with the receptor binding domain of spike protein from a chimera construct of SARS-CoV-1 and SARS-CoV-2 (PDB entry 6VW1). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10905033 10 µs simulation of the SARS-CoV-2-ACE2 complex in aqueous solution (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated from ACE2 in complex with with the receptor binding domain of spike protein SARS-COV-2 (PDB entry 6M17). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10875753 10 µs simulation trajectory of the human ACE2 ectodomain, no water or ions (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated in an apo open state (PDB entry 1R42). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### A 10 µs simulation of a SARS-CoV-1 and SARS-CoV-2 chimera-ACE2 complex, no water or ions (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated from ACE2 in complex with with the receptor binding domain of spike protein from a chimera construct of SARS-CoV-1 and SARS-CoV-2 (PDB entry 6VW1). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10875754 10 µs simulation trajectory of the human ACE2 ectodomain in aqueous solution (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated in an inhibitor-bound closed state (PDB entry 1R4L). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

### No Targets Recorded

#### DESRES-ANTON-10918441 2 µs simulations of 78 FDA approved or investigational drug molecules binding to the ectodomain of human ACE2, no water or ions (2 µs )

##### 78 2 µs trajectories of FDA approved or investigational drug molecules that in simulation remained bound to the ectodomain of human ACE2 at positions that might conceivably allosterically disrupt the interaction between these proteins. The small molecule drugs and their initial binding poses were chosen from a combination of molecular dynamics simulation and docking performed using an FDA-investigational drug library. The 78 putative ACE2 binding small molecules located at three regions on ACE2: a pocket underneath a helical bundle (residue 20-100; 51 molecules), a pocket involving a beta-hairpin structure (residue 346 to 360; 14 molecules) and a pocket behind a loop (residue 131-142; 13 molecules). The helical bundle and the beta-hairpin structure are known to interact with the RBD (receptor binding domain) of the spike protein and the loop structure is known to be involved in ACE2 homo-dimerization. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for small molecules. The C- and N-peptide termini were capped with amide and acetyl groups respectively. The ectodomain of human ACE2 is from PDB entry 6VW1. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10918441 2 µs simulations of 78 FDA approved or investigational drug molecules binding to the ectodomain of human ACE2 (2 µs )

##### 78 2 µs trajectories of FDA approved or investigational drug molecules that in simulation remained bound to the ectodomain of human ACE2 at positions that might conceivably allosterically disrupt the interaction between these proteins. The small molecule drugs and their initial binding poses were chosen from a combination of molecular dynamics simulation and docking performed using an FDA-investigational drug library. The 78 putative ACE2 binding small molecules located at three regions on ACE2: a pocket underneath a helical bundle (residue 20-100; 51 molecules), a pocket involving a beta-hairpin structure (residue 346 to 360; 14 molecules) and a pocket behind a loop (residue 131-142; 13 molecules). The helical bundle and the beta-hairpin structure are known to interact with the RBD (receptor binding domain) of the spike protein and the loop structure is known to be involved in ACE2 homo-dimerization. The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for small molecules. The C- and N-peptide termini were capped with amide and acetyl groups respectively. The ectodomain of human ACE2 is from PDB entry 6VW1. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10857295 75 µs conventional MD simulation of a chimeric RBD in complex with ACE2, no water or ions (75 µs )

##### SARS-CoV-2 attachment to host cells is mediated by a protein-protein interaction between the receptor-binding domain (RBD) of the SARS-CoV-2 spike and the human ACE2 receptor. We performed a 75 µs conventional MD simulation of a chimeric RBD in complex with ACE2 (PDB entry 6VW1). In the simulation the complex was stable, and no dissociation events were observed. We provide below the conventional MD simulation. The complex model was solvated in a ~140 Å box of 200 mM NaCl and water, and parameterized with the DES-Amber protein and ion force field, the TIP4P-D water model, and an in-house force field derived from GAFF. Simulations were performed under the NPT ensemble at 300 K. During the AWE simulations, we used a 100.8 ps resampling interval to enhance the sampling of (i) the distance between the RBD and ACE2 centers of mass, (ii) the total number of atomic contacts between the RBD and ACE2, and (iii) the complex pRMSD (the square root of the product of the RMSD of the RBD after aligning on ACE2 and the RMSD of ACE2 after aligning on the RBD).
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3001water0.2DES-Amber
TIP4P-D
Modified GAFF

### Blocking SARS-CoV-2 Spike protein binding to human ACE2 receptor

#### DESRES-ANTON-10905033 10 µs simulation of the SARS-CoV-2-ACE2 complex in aqueous solution (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated from ACE2 in complex with with the receptor binding domain of spike protein SARS-COV-2 (PDB entry 6M17). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF

#### DESRES-ANTON-10905033 10 µs simulation of the SARS-CoV-2-ACE2 complex, no water or ions (10 µs )

##### 10 µs simulation trajectory of the human ACE2 ectodomain was initiated from ACE2 in complex with with the receptor binding domain of spike protein SARS-COV-2 (PDB entry 6M17). The simulations used the Amber ff99SB-ILDN force field for proteins, the CHARMM TIP3P model for water, and the generalized Amber force field for glycosylated asparagine. The C- and A- peptide termini, including those exposed due to missing loops in the published structural models, are capped with amide and acetyl groups respectively. The system was neutralized and salted with NaCl, with a final concentration of 0.15 M. The interval between frames is 1.2 ns. The simulations were conducted at 310 K in the NPT ensemble.
TypeEnsembleTemperature (K)Pressure (atm)SolventSalinity (M)Force Fields
Molecular DynamicsNPT3101water0.15Amber99sb-ildn
TIP3P
GAFF