Relative free energy of binding and binding mode calculations of HIV-1 RT inhibitors based on dock-MM-PB/GS

2004 ◽  
Vol 57 (3) ◽  
pp. 493-503 ◽  
Author(s):  
Zhigang Zhou ◽  
Jeffry D. Madura
Keyword(s):  
Free Energy ◽  
Binding Mode ◽  
Relative Free Energy ◽  
Rt Inhibitors ◽  
Free Energy Of Binding ◽  
Hiv 1

scholarly journals Relative free energy of binding between antimicrobial peptides and SDS or DPC micelles

2009 ◽  
Vol 35 (10-11) ◽  
pp. 986-997 ◽  
Author(s):  
Abdallah Sayyed-Ahmad ◽  
Himanshu Khandelia ◽  
Yiannis N. Kaznessis
Keyword(s):  
Free Energy ◽  
Antimicrobial Peptides ◽  
Relative Free Energy ◽  
Free Energy Of Binding

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 Ligand deconstruction: Why some fragment binding positions are conserved and others are not

2015 ◽  
Vol 112 (20) ◽  
pp. E2585-E2594 ◽  
Author(s):  
Dima Kozakov ◽  
David R. Hall ◽  
Stefan Jehle ◽  
Lingqi Luo ◽  
Stefan O. Ochiana ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Hot Spot ◽  
Binding Mode ◽  
Binding Potential ◽  
Binding Modes ◽  
Affinity Ligand ◽  
Ligand Binding Sites ◽  
Free Energy Of Binding

Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

Simple, Intuitive Calculations of Free Energy of Binding for Protein−Ligand Complexes. 3. The Free Energy Contribution of Structural Water Molecules in HIV-1 Protease Complexes

2004 ◽  
Vol 47 (18) ◽  
pp. 4507-4516 ◽  
Author(s):  
Micaela Fornabaio ◽  
Francesca Spyrakis ◽  
Andrea Mozzarelli ◽  
Pietro Cozzini ◽  
Donald J. Abraham ◽  
...  
Keyword(s):  
Free Energy ◽  
Water Molecules ◽  
Energy Contribution ◽  
Structural Water ◽  
Free Energy Contribution ◽  
Free Energy Of Binding ◽  
Hiv 1

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>

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

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