scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

2020 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Luc-Henri Jolly ◽  
Étienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Nucleocapsid Protein ◽  
Extended Form ◽  
Polarizable Force Field ◽  
Relative Free Energy ◽  
Nmr Structures ◽  
Reference Protein ◽  
Energy Simulations ◽  
Hiv 1 ◽  
Most Probable Structure

Using polarizable (AMOEBA) and non-polarizable (CHARMM) force fields, we compare the relative free-energy stability of two extreme conformations of the HIV-1 NCp7 nucleocapsid that had been previously experimentally advocated to prevail in solution. Using accelerated sampling techniques, we show that they differ in stability by no more than 0.75-1.9 kcal/mol depending on the reference protein sequence. While the extended form appears to be the most probable structure, both forms should thus coexist in water explaining the differing NMR findings.<br>

scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

2020 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Luc-Henri Jolly ◽  
Étienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Nucleocapsid Protein ◽  
Extended Form ◽  
Polarizable Force Field ◽  
Relative Free Energy ◽  
Nmr Structures ◽  
Reference Protein ◽  
Energy Simulations ◽  
Hiv 1 ◽  
Most Probable Structure

Using polarizable (AMOEBA) and non-polarizable (CHARMM) force fields, we compare the relative free-energy stability of two extreme conformations of the HIV-1 NCp7 nucleocapsid that had been previously experimentally advocated to prevail in solution. Using accelerated sampling techniques, we show that they differ in stability by no more than 0.75-1.9 kcal/mol depending on the reference protein sequence. While the extended form appears to be the most probable structure, both forms should thus coexist in water explaining the differing NMR findings.<br>

scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

2020 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Luc-Henri Jolly ◽  
Étienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Nucleocapsid Protein ◽  
Extended Form ◽  
Polarizable Force Field ◽  
Relative Free Energy ◽  
Nmr Structures ◽  
Reference Protein ◽  
Energy Simulations ◽  
Hiv 1 ◽  
Most Probable Structure

Using polarizable (AMOEBA) and non-polarizable (CHARMM) force fields, we compare the relative free-energy stability of two extreme conformations of the HIV-1 NCp7 nucleocapsid that had been previously experimentally advocated to prevail in solution. Using accelerated sampling techniques, we show that they differ in stability by no more than 0.75-1.9 kcal/mol depending on the reference protein sequence. While the extended form appears to be the most probable structure, both forms should thus coexist in water explaining the differing NMR findings.<br>

scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein NCp7 Using Extensive Polarizable Force Field Free-Energy Simulations

2020 ◽  
Vol 16 (4) ◽  
pp. 2013-2020 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardère ◽  
Luc-Henri Jolly ◽  
Etienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Nucleocapsid Protein ◽  
Polarizable Force Field ◽  
Nmr Structures ◽  
Energy Simulations ◽  
Hiv 1

scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

2019 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Luc-Henri Jolly ◽  
Étienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Water Solution ◽  
Energy Difference ◽  
Umbrella Sampling ◽  
Energy Stability ◽  
Functional Protein ◽  
Relative Free Energy ◽  
Energy Simulations ◽  
Experimental Findings

The Human Immunodeficiency Virus Type 1 nucleocapsid 7 (NCp7) is a multi-functional protein formed by N-terminal and C-terminal domains surrounding two Zn-fingers, linked by a stretch of basic residues, which play a key role in the viral replication. We report the first NCp7 polarizable molecular dynamics (MD) study using the AMOEBA force field complemented by non-polarizable CHARMM simulations. Specifically, we compared the relative free-energy stability of two extreme conformations: a compact one having two aromatic residues from each finger, partially stacked, denoted A; and an unfolded one, with the two residues apart, denoted B. Each of these conformations had been previously experimentally advocated to prevail in solution. We compared their theoretical relative free-energy stability using accelerated MD sampling techniques (Steered MD and Umbrella Sampling) and showed that there was a low free energy difference between them. As A and B do not differ in stability by more than 1-1.5 kcal/mol, they should thus coexist in water solution reconciling earlier NMR experimental findings.

scholarly journals Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 920
Author(s):  
Qinfang Sun ◽  
Ronald M. Levy ◽  
Karen A. Kirby ◽  
Zhengqiang Wang ◽  
Stefan G. Sarafianos ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Energy Cost ◽  
Binding Free Energy ◽  
Resistance Mutation ◽  
Side Chain ◽  
Ligand Interaction ◽  
Energy Simulations ◽  
Hiv 1

While drug resistance mutations can often be attributed to the loss of direct or solvent-mediated protein−ligand interactions in the drug-mutant complex, in this study we show that a resistance mutation for the picomolar HIV-1 capsid (CA)-targeting antiviral (GS-6207) is mainly due to the free energy cost of the drug-induced protein side chain reorganization in the mutant protein. Among several mutations, M66I causes the most suppression of the GS-6207 antiviral activity (up to ~84,000-fold), and only 83- and 68-fold reductions for PF74 and ZW-1261, respectively. To understand the molecular basis of this drug resistance, we conducted molecular dynamics free energy simulations to study the structures, energetics, and conformational free energy landscapes involved in the inhibitors binding at the interface of two CA monomers. To minimize the protein−ligand steric clash, the I66 side chain in the M66I−GS-6207 complex switches to a higher free energy conformation from the one adopted in the apo M66I. In contrast, the binding of GS-6207 to the wild-type CA does not lead to any significant M66 conformational change. Based on an analysis that decomposes the absolute binding free energy into contributions from two receptor conformational states, it appears that it is the free energy cost of side chain reorganization rather than the reduced protein−ligand interaction that is largely responsible for the drug resistance against GS-6207.

Free energy simulations with the AMOEBA polarizable force field and metadynamics on GPU platform

2015 ◽  
Vol 37 (6) ◽  
pp. 614-622 ◽  
Author(s):  
Xiangda Peng ◽  
Yuebin Zhang ◽  
Huiying Chu ◽  
Guohui Li
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Polarizable Force Field ◽  
Energy Simulations

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

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