Computational Simulations on the Binding and Reactivity of a Nitrile Inhibitor of SARS-CoV-2 Main Protease

2021 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
José Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Free Energy ◽  
Computational Analysis ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
The Novel ◽  
Computational Simulations ◽  
Main Protease ◽  
3Cl Protease ◽  
Alchemical Free Energy ◽  
Alchemical Free Energy Calculations

We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions...

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.

scholarly journals A Hybrid Alchemical Free Energy and Machine Learning Methodology for the Calculation of Absolute Hydration Free Energies of Small Molecules

2020 ◽  
Author(s):  
Jenke Scheen ◽  
Wilson Wu ◽  
Antonia S. J. S. Mey ◽  
Paolo Tosco ◽  
Mark Mackey ◽  
...  
Keyword(s):  
Machine Learning ◽  
Free Energy ◽  
Free Energy Calculations ◽  
Learning Approaches ◽  
Free Energies ◽  
Training Set ◽  
Set Size ◽  
Correction Terms ◽  
Alchemical Free Energy ◽  
Alchemical Free Energy Calculations

A methodology that combines alchemical free energy calculations (FEP) with machine learning (ML) has been developed to compute accurate absolute hydration free energies. The hybrid FEP/ML methodology was trained on a subset of the FreeSolv database, and retrospectively shown to outperform most submissions from the SAMPL4 competition. Compared to pure machine-learning approaches, FEP/ML yields more precise estimates of free energies of hydration, and requires a fraction of the training set size to outperform standalone FEP calculations. The ML-derived correction terms are further shown to be transferable to a range of related FEP simulation protocols. The approach may be used to inexpensively improve the accuracy of FEP calculations, and to flag molecules which will benefit the most from bespoke forcefield parameterisation efforts.

Thermodynamic Stability of Human γD-Crystallin Mutants Using Alchemical Free-Energy Calculations

2019 ◽  
Vol 123 (27) ◽  
pp. 5671-5677 ◽  
Author(s):  
Rodrigo Aguayo-Ortiz ◽  
Augusto González-Navejas ◽  
Giovanni Palomino-Vizcaino ◽  
Oscar Rodriguez-Meza ◽  
Miguel Costas ◽  
...  
Keyword(s):  
Free Energy ◽  
Thermodynamic Stability ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Alchemical Free Energy ◽  
Alchemical Free Energy Calculations
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