scholarly journals On the Role of Water Models in Quantifying the Binding Free Energy of Highly Conserved Water Molecules in Proteins: The Case of Concanavalin A

2011 ◽  
Vol 7 (10) ◽  
pp. 3391-3398 ◽  
Author(s):  
Elisa Fadda ◽  
Robert J. Woods
Keyword(s):  
Free Energy ◽  
Concanavalin A ◽  
Binding Free Energy ◽  
Water Molecules ◽  
Conserved Water Molecules ◽  
Water Models

scholarly journals Conserved Water Molecules Stabilize the Ω-Loop in Class A β-Lactamases

2008 ◽  
Vol 52 (3) ◽  
pp. 1072-1079 ◽  
Author(s):  
Fabian Bös ◽  
Jürgen Pleiss
Keyword(s):  
Phylogenetic Analysis ◽  
High Resolution ◽  
Evolutionary Relationship ◽  
Water Molecules ◽  
Protein Residues ◽  
Class A ◽  
Conserved Water Molecules ◽  
Dense Cluster ◽  
The Relationship

ABSTRACT A set of 49 high-resolution (≤2.2 Å) structures of the TEM, SHV, and CTX-M class A β-lactamase families was systematically analyzed to investigate the role of conserved water molecules in the stabilization of the Ω-loop. Overall, 13 water molecules were found to be conserved in at least 45 structures, including two water positions which were found to be conserved in all structures. Of the 13 conserved water molecules, 6 are located at the Ω-loop, forming a dense cluster with hydrogen bonds to residues at the Ω-loop as well as to the rest of the protein. This layer of conserved water molecules is packed between the Ω-loop and the rest of the protein and acts as structural glue, which could reduce the flexibility of the Ω-loop. A correlation between conserved water molecules and conserved protein residues could in general not be detected, with the exception of the conserved water molecules at the Ω-loop. Furthermore, the evolutionary relationship between the three families, derived from the number of conserved water molecules, is similar to the relationship derived from phylogenetic analysis.

scholarly journals On the Role of Dewetting Transitions in Host–Guest Binding Free Energy Calculations

2012 ◽  
Vol 9 (1) ◽  
pp. 46-53 ◽  
Author(s):  
Kathleen E. Rogers ◽  
Juan Manuel Ortiz-Sánchez ◽  
Riccardo Baron ◽  
Mikolai Fajer ◽  
César Augusto F. de Oliveira ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Guest Binding ◽  
Binding Free Energy Calculations

scholarly journals Intriguing Role of Water in Plant Hormone Perception

2021 ◽  
Author(s):  
Chuankai Zhao ◽  
Diego Eduardo Kleiman ◽  
Diwakar Shukla
Keyword(s):  
Free Energy ◽  
Plant Growth ◽  
Binding Site ◽  
Plant Hormones ◽  
Plant Hormone ◽  
Water Molecules ◽  
Water Displacement ◽  
Dynamics Simulations ◽  
Free Energy Of Binding

Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. Plant hormones are specifically recognized by the binding site of their receptors. In this work, we investigated the role of water displacement and reorganization at the binding site of plant receptors on the binding of eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) using extensive molecular dynamics simulations and inhomogeneous solvation theory. Our findings demonstrated that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with free energy barriers. Also, our results have shown that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncov- ers the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.

scholarly journals Effects of Water Models on Binding Affinity: Evidence from All-Atom Simulation of Binding of Tamiflu to A/H5N1 Neuraminidase

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Trang Truc Nguyen ◽  
Man Hoang Viet ◽  
Mai Suan Li
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Force Fields ◽  
Binding Free Energy ◽  
Molecular Mechanic ◽  
Water Density ◽  
Wild Type ◽  
Oseltamivir Carboxylate ◽  
Water Models

The influence of water models SPC, SPC/E, TIP3P, and TIP4P on ligand binding affinity is examined by calculating the binding free energyΔGbindof oseltamivir carboxylate (Tamiflu) to the wild type of glycoprotein neuraminidase from the pandemic A/H5N1 virus.ΔGbindis estimated by the Molecular Mechanic-Poisson Boltzmann Surface Area method and all-atom simulations with different combinations of these aqueous models and four force fields AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L. It is shown that there is no correlation between the binding free energy and the water density in the binding pocket in CHARMM. However, for three remaining force fieldsΔGbinddecays with increase of water density. SPC/E provides the lowest binding free energy for any force field, while the water effect is the most pronounced in CHARMM. In agreement with the popular GROMACS recommendation, the binding score obtained by combinations of AMBER-TIP3P, OPLS-TIP4P, and GROMOS-SPC is the most relevant to the experiments. For wild-type neuraminidase we have found that SPC is more suitable for CHARMM than TIP3P recommended by GROMACS for studying ligand binding. However, our study for three of its mutants reveals that TIP3P is presumably the best choice for CHARMM.

scholarly journals Application of ESMACS Binding Free Energy Protocols to Diverse Datasets: Bromodomain-Containing Protein 4

2019 ◽  
Author(s):  
David Wright ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
Gary Tresadern ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Water Molecules ◽  
Calculation Data ◽  
Simulation Input ◽  
Explicit Water ◽  
Entropic Contribution

<div>We investigate the robustness of our ensemble molecular dynamics binding free energy protocols, known as ESMACS, to different choices of forcefield, starting structure and analysis. ESMACS is based on MMPBSA and we examinge the influence of multiple trajectories, explicit water molecules and estimates of the entropic contribution to the binding free energy.</div><div><br></div><div>Simulation input and binding affinity calculation data:</div>https://doi.org/10.5281/zenodo.1484050

scholarly journals Application of ESMACS Binding Free Energy Protocols to Diverse Datasets: Bromodomain-Containing Protein 4

2019 ◽  
Author(s):  
David Wright ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
Gary Tresadern ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Water Molecules ◽  
Calculation Data ◽  
Simulation Input ◽  
Explicit Water ◽  
Entropic Contribution

<div>We investigate the robustness of our ensemble molecular dynamics binding free energy protocols, known as ESMACS, to different choices of forcefield, starting structure and analysis. ESMACS is based on MMPBSA and we examinge the influence of multiple trajectories, explicit water molecules and estimates of the entropic contribution to the binding free energy.</div><div><br></div><div>Simulation input and binding affinity calculation data:</div>https://doi.org/10.5281/zenodo.1484050

scholarly journals Accounting for the Central Role of Interfacial Water in Protein-Ligand Binding Free Energy Calculations

2020 ◽  
Author(s):  
Ido Ben-Shalom ◽  
Zhixiong Lin ◽  
Brian Radak ◽  
Charles Lin ◽  
Woody Sherman ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Site ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Computer Hardware ◽  
Water Molecules ◽  
Energy Calculations ◽  
Binding Free Energy Calculations

Rigorous binding free energy methods in drug discovery are growing in popularity due to a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all the binding site is inaccessible to bulk solvent, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD. This sampling limitation is problematic in relative binding free energy calculations, which compute the reversible work of converting Ligand 1 to Ligand 2 within the binding site. Thus, if Ligand 1 is smaller and/or more polar than Ligand 2, the perturbation may allow additional water molecules to occupy a region of the binding site. However, this change in hydration may not be captured by standard MD simulations and may therefore lead to errors in the computed free energy. We recently developed a hybrid Monte Carlo/MD (MC/MD) method, which speeds the equilibration of water between bulk solvent and buried cavities, while sampling from the intended distribution of states. Here, we report on the use of this approach in the context of alchemical binding free energy calculations. We find that using MC/MD markedly improves the accuracy of the calculations and also reduces hysteresis between the forward and reverse perturbations, relative to matched calculations using only MD with or without the crystallographic water molecules. The present method is available for use in the AMBER simulation software.<br>

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