GPU-Accelerated Molecular Dynamics and Free Energy Methods in Amber18: Performance Enhancements and New Features

T, Lee; Cerutti, David S.; Mermelstein, Dan; Lin, Charles; LeGrand, Scott; Giese, Timothy J.; Roitberg, Adrián E.; Case, David A.; Walker, Ross C.; York, Darrin M.

doi:10.1021/acs.jcim.8b00462

Cited by 355 publications

(332 citation statements)

References 68 publications

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“…XFEP 31 coupled with Amber-TI [32][33][34][35][36] was used to calculate the relative binding free energies. The crystal structures S protein RBD on both SARS-CoV and SARS-CoV-2 complexed with ACE2, in addition to the last frame from the 100 ns simulation of SARS-CoV-2 S RBD/ACE2 were used as the starting structures.…”

Section: Relative Binding Free Energy Calculationsmentioning

confidence: 99%

Computational Prediction of Mutational Effects on the SARS-CoV-2 Binding by Relative Free Energy Calculations

Zou¹,

Yin²,

Fang³

et al. 2020

Preprint

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The ability of coronaviruses infecting humans is invariably associated with their binding strengths to human receptor proteins. Both SARS-CoV-2, initially named 2019-nCoV, and SARS-CoV were reported to utilize angiotensin-converting enzyme 2 (ACE2) as the entry receptor of human cells. To better understand the interplay between SARS-CoV-2 and ACE2, we performed computational alanine scanning mutagenesis, on the "hotspot" residues at protein-protein interfaces, by relative free energy calculations. Our results suggested that the binding strengths of SARS-CoV and SARS-CoV-2 to the host receptor are comparable. Free energy calculations showed a promise in assessing the infectious ability of viruses on a physical basis, and can also provide useful information for the design of antiviral drugs.

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Section: Relative Binding Free Energy Calculationsmentioning

confidence: 99%

Computational Prediction of Mutational Effects on the SARS-CoV-2 Binding by Relative Free Energy Calculations

Zou¹,

Yin²,

Fang³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…XFEP 31 coupled with Amber-TI [32][33][34][35][36] was used to calculate the relative binding free energies. The crystal structures S protein RBD on both SARS-CoV and SARS-CoV-2 complexed with ACE2 and the last frame from the 100 ns simulation of SARS-CoV-2 S RBD/ACE2 were used as the starting structures.…”

Section: Relative Binding Free Energy Calculationsmentioning

confidence: 99%

Computational Prediction of Mutational Effects on the SARS-CoV-2 Binding by Relative Free Energy Calculations

Zou¹,

Yin²,

Fang³

et al. 2020

Preprint

View full text Add to dashboard Cite

The ability of coronaviruses to infect humans is invariably associated with their binding strengths to human receptor proteins. Both SARS-CoV-2, initially named 2019-nCoV, and SARS-CoV were reported to utilize angiotensin-converting enzyme 2 (ACE2) as an entry receptor in human cells. To better understand the interplay between SARS-CoV-2 and ACE2, we performed computational alanine scanning mutagenesis on the "hotspot" residues at protein-protein interfaces using relative free energy calculations. Our data suggest that the mutations in SARS-CoV-2 lead to a greater binding affinity relative to SARS-CoV. In addition, our free energy calculations provide insight into the infectious ability of viruses on a physical basis, and also provide useful information for the design of antiviral drugs.

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“…This method helps in nding the underlying dynamics and how it is connected to enzyme's biomolecular function [23][24] [25]. AMBER 18 [26] simulation package was used to execute 200 ns MD simulations on all the prepared complexes using (Graphics Processing Unit) GPU accelerated version of Partial Mesh Ewald Molecular Dynamics (PMEMD) simulations [27]. The ff99SB [28] and the general AMBER force elds (GAFF) [29] [30] were employed to parametrize the enzyme and the considered ligands using LEaP implemented in Amber 18.…”

Section: Simulationsmentioning

confidence: 99%

ABBV-744 and Onalespid as Potential Inhibitors of SARS-CoV-2 main Protease Enzyme: A Promising Therapeutics in COVID-19?

Fakhar¹,

Khan²,

Ahmad³

2020

Preprint

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A new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening work-flow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the best hit compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered compounds. Binding studies revealed that compound ABBV-744 binds to the Mpro with strong affinity (Gbind -45.43 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

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GPU-Accelerated Molecular Dynamics and Free Energy Methods in Amber18: Performance Enhancements and New Features

Cited by 355 publications

References 68 publications

Computational Prediction of Mutational Effects on the SARS-CoV-2 Binding by Relative Free Energy Calculations

Computational Prediction of Mutational Effects on the SARS-CoV-2 Binding by Relative Free Energy Calculations

Computational Prediction of Mutational Effects on the SARS-CoV-2 Binding by Relative Free Energy Calculations

ABBV-744 and Onalespid as Potential Inhibitors of SARS-CoV-2 main Protease Enzyme: A Promising Therapeutics in COVID-19?

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