scholarly journals Optimization of Protein–Ligand Electrostatic Interactions Using an Alchemical Free-Energy Method

2019 ◽  
Vol 15 (11) ◽  
pp. 6504-6512 ◽  
Author(s):  
Alexander D. Wade ◽  
David J. Huggins
Keyword(s):  
Free Energy ◽  
Energy Method ◽  
Electrostatic Interactions ◽  
Alchemical Free Energy

scholarly journals Optimization of Protein-Ligand Electrostatic Interactions Using an Alchemical Free-Energy Method

2019 ◽  
Author(s):  
Alexander Wade ◽  
David Huggins
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Energy Method ◽  
Electrostatic Interactions ◽  
Protein Complexes ◽  
Chemical Changes ◽  
Average Improvement ◽  
Explicit Solvent ◽  
Energy Perturbation ◽  
Alchemical Free Energy

<p>We present an alchemical free-energy method for optimizing the partial charges of a ligand to maximize the binding affinity with a receptor. This methodology can be applied to known ligand-protein complexes to determine an optimized set of ligand partial atomic changes. Three protein-ligand complexes have been optimized in this work: FXa, P38 and androgen receptor. The optimization of the ligand charges yielded improvements to binding affinity for all three systems. The sets of optimized charges can be used to identify design principles for chemical changes to the ligand which improve the binding affinity. In this work, beneficial chemical mutations are generated from these principles and the resulting molecules tested using free-energy perturbation calculations. We show that three quarters of our chemical changes are predicted to improve the binding affinity, with an average improvement of approximately 1 kcal/mol. The results demonstrate that charge optimization in explicit solvent is a useful tool for predicting beneficial chemical changes such as pyridinations, fluorinations, and oxygen to sulphur mutations. </p>

scholarly journals Optimization of Protein-Ligand Electrostatic Interactions Using an Alchemical Free-Energy Method

2019 ◽  
Author(s):  
Alexander Wade ◽  
David Huggins
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Energy Method ◽  
Electrostatic Interactions ◽  
Protein Complexes ◽  
Chemical Changes ◽  
Average Improvement ◽  
Explicit Solvent ◽  
Energy Perturbation ◽  
Alchemical Free Energy

<p>We present an alchemical free-energy method for optimizing the partial charges of a ligand to maximize the binding affinity with a receptor. This methodology can be applied to known ligand-protein complexes to determine an optimized set of ligand partial atomic changes. Three protein-ligand complexes have been optimized in this work: FXa, P38 and androgen receptor. The optimization of the ligand charges yielded improvements to binding affinity for all three systems. The sets of optimized charges can be used to identify design principles for chemical changes to the ligand which improve the binding affinity. In this work, beneficial chemical mutations are generated from these principles and the resulting molecules tested using free-energy perturbation calculations. We show that three quarters of our chemical changes are predicted to improve the binding affinity, with an average improvement of approximately 1 kcal/mol. The results demonstrate that charge optimization in explicit solvent is a useful tool for predicting beneficial chemical changes such as pyridinations, fluorinations, and oxygen to sulphur mutations. </p>

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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