scholarly journals Effect of Atomic Charges on Octanol–Water Partition Coefficient Using Alchemical Free Energy Calculation

Molecules ◽  
2018 ◽  
Vol 23 (2) ◽  
pp. 425 ◽  
Author(s):  
Koji Ogata ◽  
Makoto Hatakeyama ◽  
Shinichiro Nakamura
Keyword(s):  
Free Energy ◽  
Partition Coefficient ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Atomic Charges ◽  
Water Partition Coefficient ◽  
Alchemical Free Energy

scholarly journals Implementation of the QUBE Force Field for High-Throughput Alchemical Free Energy Calculations

2020 ◽  
Author(s):  
Lauren Nelson ◽  
Sofia Bariami ◽  
Chris Ringrose ◽  
Joshua Horton ◽  
Vadiraj Kurdekar ◽  
...  
Keyword(s):  
Free Energy ◽  
Force Field ◽  
High Throughput ◽  
Potential Energy Function ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Alchemical Free Energy ◽  
Simulation Package

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field approach has been developed to facilitate the automated derivation of potential energy function parameters for modelling protein-ligand binding. To date the approach has been validated in the context of Monte Carlo simulations of protein-ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free energy calculation molecular dynamics simulation package SOMD. The implementation is validated by computing relative binding free energies for two congeneric series of non-nucleoside inhibitors of HIV-1 reverse transcriptase using QUBE and AMBER/GAFF force fields. The availability of QUBE in a modern simulation package that makes efficient use of GPU acceleration will greatly facilitate future high-throughput alchemical free energy calculation studies.</p></div></div></div>

scholarly journals Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0213217 ◽  
Author(s):  
José M. Granadino-Roldán ◽  
Antonia S. J. S. Mey ◽  
Juan J. Pérez González ◽  
Stefano Bosisio ◽  
Jaime Rubio-Martinez ◽  
...  
Keyword(s):  
Free Energy ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Set Up ◽  
Alchemical Free Energy

scholarly journals Synergistic approach to improve “alchemical” free energy calculation in rugged energy surface

2007 ◽  
Vol 126 (14) ◽  
pp. 144109 ◽  
Author(s):  
Donghong Min ◽  
Hongzhi Li ◽  
Guohui Li ◽  
Ryan Bitetti-Putzer ◽  
Wei Yang
Keyword(s):  
Free Energy ◽  
Energy Surface ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Synergistic Approach ◽  
Alchemical Free Energy

scholarly journals Expanded Ensemble Methods Can Be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies

2021 ◽  
Author(s):  
Si Zhang ◽  
David Hahn ◽  
Michael R. Shirts ◽  
Vincent Voelz
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Ensemble Methods ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Free Energies ◽  
Relative Binding ◽  
Alchemical Free Energy ◽  
Binding Free Energies ◽  
Expanded Ensemble

<p>Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. In this paper, as a test of expanded ensemble methods, we computed relative binding free energies using the Open Force Field Initiative force field (codename “Parsley”) for twenty-four pairs of Tyk2 inhibitors derived from a congeneric series of 16 compounds. The EE predictions agree well with the experimental values (RMSE of 0.94 ± 0.13 kcal mol<sup>−1</sup> and MUE of 0.75 ± 0.12 kcal mol<sup>−1</sup>). We find that while increasing the number of alchemical intermediates can improve the phase space overlap, faster convergence can be obtained with fewer intermediates, as long as the acceptance rates are sufficient. We find that convergence can be improved using more aggressive updating of the biases, and that estimates can be improved by performing multiple independent EE calculations. This work demonstrates that EE is a viable option for alchemical free energy calculation. We discuss the implications of these findings for rational drug design, as well as future directions for improvement.</p>

scholarly journals Expanded Ensemble Methods Can Be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies

2021 ◽  
Author(s):  
Si Zhang ◽  
David Hahn ◽  
Michael R. Shirts ◽  
Vincent Voelz
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Ensemble Methods ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Free Energies ◽  
Relative Binding ◽  
Alchemical Free Energy ◽  
Binding Free Energies ◽  
Expanded Ensemble

<p>Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. In this paper, as a test of expanded ensemble methods, we computed relative binding free energies using the Open Force Field Initiative force field (codename “Parsley”) for twenty-four pairs of Tyk2 inhibitors derived from a congeneric series of 16 compounds. The EE predictions agree well with the experimental values (RMSE of 0.94 ± 0.13 kcal mol<sup>−1</sup> and MUE of 0.75 ± 0.12 kcal mol<sup>−1</sup>). We find that while increasing the number of alchemical intermediates can improve the phase space overlap, faster convergence can be obtained with fewer intermediates, as long as the acceptance rates are sufficient. We find that convergence can be improved using more aggressive updating of the biases, and that estimates can be improved by performing multiple independent EE calculations. This work demonstrates that EE is a viable option for alchemical free energy calculation. We discuss the implications of these findings for rational drug design, as well as future directions for improvement.</p>

scholarly journals Gibbs Sampler-Based λ-Dynamics and Rao–Blackwell Estimator for Alchemical Free Energy Calculation

2017 ◽  
Vol 13 (6) ◽  
pp. 2501-2510 ◽  
Author(s):  
Xinqiang Ding ◽  
Jonah Z. Vilseck ◽  
Ryan L. Hayes ◽  
Charles L. Brooks
Keyword(s):  
Free Energy ◽  
Gibbs Sampler ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Alchemical Free Energy

scholarly journals Implementation of the QUBE Force Field for High-Throughput Alchemical Free Energy Calculations

2020 ◽  
Author(s):  
Lauren Nelson ◽  
Sofia Bariami ◽  
Chris Ringrose ◽  
Joshua Horton ◽  
Vadiraj Kurdekar ◽  
...  
Keyword(s):  
Free Energy ◽  
Force Field ◽  
High Throughput ◽  
Potential Energy Function ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Alchemical Free Energy ◽  
Simulation Package

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field approach has been developed to facilitate the automated derivation of potential energy function parameters for modelling protein-ligand binding. To date the approach has been validated in the context of Monte Carlo simulations of protein-ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free energy calculation molecular dynamics simulation package SOMD. The implementation is validated by computing relative binding free energies for two congeneric series of non-nucleoside inhibitors of HIV-1 reverse transcriptase using QUBE and AMBER/GAFF force fields. The availability of QUBE in a modern simulation package that makes efficient use of GPU acceleration will greatly facilitate future high-throughput alchemical free energy calculation studies.</p></div></div></div>

SAMPL6 Octanol-Water Partition Coefficients from Alchemical Free Energy Calculations with MBIS Atomic Charges

2019 ◽  
Author(s):  
Maximiliano Riquelme ◽  
Esteban Vöhringer-Martinez
Keyword(s):  
Free Energy ◽  
Electron Density ◽  
Free Energy Calculations ◽  
Basis Set ◽  
Energetic Cost ◽  
Atomic Charges ◽  
Free Energies ◽  
Energy Calculations ◽  
Alchemical Free Energy ◽  
Alchemical Free Energy Calculations

In molecular modeling the description of the interactions between molecules forms the basis for a correct prediction of macroscopic observables. Here, we derive atomic charges from the implicitly polarized electron density of eleven molecules in the SAMPL6 challenge using the Hirshfeld-I and Minimal Basis Set Iterative Stockholder(MBIS) partitioning method. These atomic charges combined with other parameters in the GAFF force field and different water/octanol models were then used in alchemical free energy calculations to obtain hydration and solvation free energies, which after correction for the polarization cost, result in the blind prediction of the partition coefficient. From the tested partitioning methods and water models the S-MBIS atomic charges with the TIP3P water model presented the smallest deviation from the experiment. Conformational dependence of the free energies and the energetic cost associated with the polarization of the electron density are discussed.

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