scholarly journals Unraveling the SARS-CoV-2 Main Protease Mechanism Using Multiscale DFT/MM Methods

2020 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
J. Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Active Site ◽  
Energy Landscape ◽  
Multiscale Simulation ◽  
Free Energy Landscape ◽  
Simulation Methods ◽  
Thermodynamics And Kinetics ◽  
Main Protease ◽  
Key Factor ◽  
Inhibition Process ◽  
Kinetics Of

<p>We present a detailed theoretical analysis of the reaction mechanism of proteolysis catalyzed by the main protease of SARS-CoV-2. Using multiscale simulation methods, we have characterized the interactions stablished by a peptidic substrate in the active site and then we have explored the free energy landscape associated to the acylation and de-acylation steps of the proteolysis reaction, characterizing the transition states of the process. Our mechanistic proposals can explain most of the experimental observations made on the highly similar ortholog protease of SARS-CoV. We point out to some key interactions that may facilitate the acylation process and thus can be crucial in the design of more specific and efficient inhibitors of the main protease activity. In particular, from our results, the P1’ residue can be a key factor to improve the thermodynamics and kinetics of the inhibition process.</p>

scholarly journals Unraveling the SARS-CoV-2 Main Protease Mechanism Using Multiscale DFT/MM Methods

2020 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
J. Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Active Site ◽  
Energy Landscape ◽  
Multiscale Simulation ◽  
Free Energy Landscape ◽  
Simulation Methods ◽  
Thermodynamics And Kinetics ◽  
Main Protease ◽  
Key Factor ◽  
Inhibition Process ◽  
Kinetics Of

<p>We present a detailed theoretical analysis of the reaction mechanism of proteolysis catalyzed by the main protease of SARS-CoV-2. Using multiscale simulation methods, we have characterized the interactions stablished by a peptidic substrate in the active site and then we have explored the free energy landscape associated to the acylation and de-acylation steps of the proteolysis reaction, characterizing the transition states of the process. Our mechanistic proposals can explain most of the experimental observations made on the highly similar ortholog protease of SARS-CoV. We point out to some key interactions that may facilitate the acylation process and thus can be crucial in the design of more specific and efficient inhibitors of the main protease activity. In particular, from our results, the P1’ residue can be a key factor to improve the thermodynamics and kinetics of the inhibition process.</p>

Unraveling the SARS-CoV-2 Main Protease Mechanism Using Multiscale DFT/MM Methods

2020 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
J. Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Active Site ◽  
Energy Landscape ◽  
Multiscale Simulation ◽  
Free Energy Landscape ◽  
Simulation Methods ◽  
Thermodynamics And Kinetics ◽  
Main Protease ◽  
Key Factor ◽  
Inhibition Process ◽  
Kinetics Of

<p>We present a detailed theoretical analysis of the reaction mechanism of proteolysis catalyzed by the main protease of SARS-CoV-2. Using multiscale simulation methods, we have characterized the interactions stablished by a peptidic substrate in the active site and then we have explored the free energy landscape associated to the acylation and de-acylation steps of the proteolysis reaction, characterizing the transition states of the process. Our mechanistic proposals can explain most of the experimental observations made on the highly similar ortholog protease of SARS-CoV. We point out to some key interactions that may facilitate the acylation process and thus can be crucial in the design of more specific and efficient inhibitors of the main protease activity. In particular, from our results, the P1’ residue can be a key factor to improve the thermodynamics and kinetics of the inhibition process.</p>

scholarly journals The histone H3 N-terminal tail: a computational analysis of the free energy landscape and kinetics

2015 ◽  
Vol 17 (20) ◽  
pp. 13689-13698 ◽  
Author(s):  
Yuqing Zheng ◽  
Qiang Cui
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Critical Role ◽  
Histone H3 ◽  
Free Energy Landscape ◽  
Chromatin Dynamics ◽  
Markov State Models ◽  
State Models ◽  
Dynamics Simulations ◽  
Kinetics Of

Extensive molecular dynamics simulations and Markov State models are used to characterize the free energy landscape and kinetics of the histone H3 N-terminal tail, which plays a critical role in regulating chromatin dynamics and gene activity.

scholarly journals Exploring biomolecular energy landscapes

2017 ◽  
Vol 53 (52) ◽  
pp. 6974-6988 ◽  
Author(s):  
Jerelle A. Joseph ◽  
Konstantin Röder ◽  
Debayan Chakraborty ◽  
Rosemary G. Mantell ◽  
David J. Wales
Keyword(s):  
Potential Energy ◽  
Structure Prediction ◽  
Energy Landscape ◽  
Energy Landscapes ◽  
Computational Framework ◽  
Feature Article ◽  
Thermodynamics And Kinetics ◽  
Potential Energy Landscape ◽  
Kinetics Of

This feature article presents the potential energy landscape perspective, which provides both a conceptual and computational framework for structure prediction, and decoding the global thermodynamics and kinetics of biomolecules.

scholarly journals Thermodynamics and Kinetics in Antibody Resistance of the 501Y.V2 SARS-CoV-2 Variant

2021 ◽  
Author(s):  
Son Tung Ngo ◽  
Trung Hai Nguyen ◽  
Duc-Hung Pham ◽  
Nguyen Thanh Tung ◽  
Pham Cam Nam
Keyword(s):  
Free Energy ◽  
South African ◽  
Binding Free Energy ◽  
Energy Landscape ◽  
Neutralizing Antibody ◽  
Receptor Binding Domain ◽  
The South ◽  
Thermodynamics And Kinetics ◽  
Antibody Resistance ◽  
Kinetics Of

Understanding thermodynamics and kinetics of the binding process of antibody to SARS-CoV-2 receptor-binding domain (RBD) of Spike protein is very important for the development of COVID19 vaccines. Especially, it is essential to understand how the binding mechanism may change under the effects of RBD mutations. In this context, we have demonstrated that the South African variant (B1.351 or 501Y.V2) can resist the neutralizing antibody (NAb). Three substitutions in RBD including K417N, E484K, and N501Y alters the free energy landscape, binding pose, binding free energy, binding kinetics, and unbinding pathway of RBD + NAb complexes. The low binding affinity of NAb to 501Y.V2 RBD confirms the antibody resistance of the South African variant.

scholarly journals Thermodynamics and Kinetics in Antibody Resistance of the 501Y.V2 SARS-CoV-2 Variant

2021 ◽  
Author(s):  
Son Tung Ngo ◽  
Trung Hai Nguyen ◽  
Duc-Hung Pham ◽  
Nguyen Thanh Tung ◽  
Pham Cam Nam
Keyword(s):  
Free Energy ◽  
South African ◽  
Binding Free Energy ◽  
Energy Landscape ◽  
Neutralizing Antibody ◽  
Receptor Binding Domain ◽  
The South ◽  
Thermodynamics And Kinetics ◽  
Antibody Resistance ◽  
Kinetics Of

Understanding thermodynamics and kinetics of the binding process of antibody to SARS-CoV-2 receptor-binding domain (RBD) of Spike protein is very important for the development of COVID19 vaccines. Especially, it is essential to understand how the binding mechanism may change under the effects of RBD mutations. In this context, we have demonstrated that the South African variant (B1.351 or 501Y.V2) can resist the neutralizing antibody (NAb). Three substitutions in RBD including K417N, E484K, and N501Y alters the free energy landscape, binding pose, binding free energy, binding kinetics, and unbinding pathway of RBD + NAb complexes. The low binding affinity of NAb to 501Y.V2 RBD confirms the antibody resistance of the South African variant.

scholarly journals Thermodynamics and Kinetics in Antibody Resistance of the 501Y.V2 SARS-CoV-2 Variant

2021 ◽  
Author(s):  
Son Tung Ngo ◽  
Trung Hai Nguyen ◽  
Duc-Hung Pham ◽  
Nguyen Thanh Tung ◽  
Pham Cam Nam
Keyword(s):  
Free Energy ◽  
South African ◽  
Binding Free Energy ◽  
Energy Landscape ◽  
Neutralizing Antibody ◽  
Receptor Binding Domain ◽  
The South ◽  
Thermodynamics And Kinetics ◽  
Antibody Resistance ◽  
Kinetics Of

Understanding thermodynamics and kinetics of the binding process of antibody to SARS-CoV-2 receptor-binding domain (RBD) of Spike protein is very important for the development of COVID19 vaccines. Especially, it is essential to understand how the binding mechanism may change under the effects of RBD mutations. In this context, we have demonstrated that the South African variant (B1.351 or 501Y.V2) can resist the neutralizing antibody (NAb). Three substitutions in RBD including K417N, E484K, and N501Y alters the free energy landscape, binding pose, binding free energy, binding kinetics, and unbinding pathway of RBD + NAb complexes. The low binding affinity of NAb to 501Y.V2 RBD confirms the antibody resistance of the South African variant.

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