Estimating the Roles of Protonation and Electronic Polarization in Absolute Binding Affinity Simulations.

  title={Estimating the Roles of Protonation and Electronic Polarization in Absolute Binding Affinity Simulations.},
  author={Edward King and Ruxi Qi and Han Li and Ray Luo and Eric W. Aitchison},
  journal={Journal of chemical theory and computation},
Accurate prediction of binding free energies is critical to streamlining the drug development and protein design process. With the advent of GPU acceleration, absolute alchemical methods, which simulate the removal of ligand electrostatics and van der Waals interactions with the protein, have become routinely accessible and provide a physically rigorous approach that enables full consideration of flexibility and solvent interaction. However, standard explicit solvent simulations are unable to… 

Recent Developments in Free Energy Calculations for Drug Discovery

The varied methodology of these approaches, developments enhancing simulation efficiency and reliability, remaining challenges hindering predictive performance, and applications to problems in the fields of medicine and biochemistry are reviewed.

The Importance of Charge Transfer and Solvent Screening in the Interactions of Backbones and Functional Groups in Amino Acid Residues and Nucleotides

Quantum mechanical calculations at the level of density-functional tight-binding are applied to a protein–DNA complex consisting of 3763 atoms, averaging 100 snapshots from molecular dynamics simulations and it is shown that, when solvent screening is taken into account, the contributions of the backbones are small and the binding of nucleotides in the double helix is governed by the base–base interactions.

Meta-Analysis Reveals That Absolute Binding Free-Energy Calculations Approach Chemical Accuracy.

Systematic and quantitative analysis of the reliability of formally exact methods that in silico calculate absolute protein-ligand binding free energies remains lacking. Here, we provide, for the

Transferability of the Electrostatic Parameters of the Polarizable Gaussian Multipole Model.

Accuracy and transferability are the two highly desirable properties of molecular mechanical force fields. Compared with the extensively used point-charge additive force fields that apply fixed

Identifying the Hot Spot Residues of the SARS-CoV-2 Main Protease Using MM-PBSA and Multiple Force Fields

It is identified that the residues of the S4 subsite of the binding site, N142, M165, and R188, contribute strongly to ligand binding, and the terminal residues, D295, R298, and Q299 are identified to have attractive interactions with ligands via electrostatic and solvation energy.

Accurate Reproduction of Quantum Mechanical Many-Body Interactions in Peptide Main-Chain Hydrogen-Bonding Oligomers by the Polarizable Gaussian Multipole Model.

A key advantage of polarizable force fields is their ability to model the atomic polarization effects that play key roles in the atomic many-body interactions. In this work, we assessed the accuracy

Polarization energies in the fragment molecular orbital method

Using isolated and polarized states of fragments, a method for computing the polarization energies in density functional theory (DFT) and density‐functional tight‐binding (DFTB) is developed in the



Calculation of protein-ligand binding affinities.

This paper reviews physics-based models of binding, beginning with a summary of the changes in potential energy, solvation energy, and configurational entropy that influence affinity, and a theoretical overview to frame the discussion of specific computational approaches.

Rigorous Free Energy Perturbation Approach to Estimating Relative Binding Affinities between Ligands with Multiple Protonation and Tautomeric States.

The results demonstrate that the p Ka and tautomeric state correction approach is able to rigorously and accurately incorporate multiple protonation and t Automeric states in the binding affinity calculations.

Accurate Calculation of Relative Binding Free Energies between Ligands with Different Net Charges.

The FEP algorithm is extended, which has been extensively applied to many drug discovery programs for relative binding free-energy calculations between ligands with the same net charge, to enable charge-changing perturbations and is found to be on par with the accuracy of charge-conserving perturbation.

Computation of pH‐dependent binding free energies

The theoretical framework to examine the pH dependence of protein–ligand binding processes is discussed and the physical origins and prevalence of the protonation changes upon binding are outlined.

Calculating protein–ligand binding affinities with MMPBSA: Method and error analysis

Upon correction of the binding‐induced rearrangement free energy and the binding entropy lost, the errors in absolute binding affinities were also reduced dramatically when the modern nonpolar solvent model was used, although further developments were apparently necessary to further improve the MMPBSA methods.

Ligand configurational entropy and protein binding

Using Mining Minima calculations to analyze the association of amprenavir with HIV protease highlights the potential to gain affinity by designing conformationally restricted ligands and has implications for the formulation of energy models for ligand scoring.

Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations

This work evaluated the performance of free energy calculations based on molecular dynamics for the prediction of selectivity by estimating the affinity profile of three bromodomain inhibitors across multiple bromidomain families, and by comparing the results to isothermal titration calorimetry data.

Balancing solvation and intramolecular interactions: toward a consistent generalized Born force field.

It is demonstrated that it is possible to achieve a balanced implicit solvent force field by further optimizing the input atomic radii in combination with adjusting the protein backbone torsional energetics.

Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10.

A Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the F EP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs).

Absolute Binding Free Energies: A Quantitative Approach for Their Calculation

A versatile set of restraints is described that can be used in MD simulations, that restricts both the position and the orientation of the ligand, and that is defined relative to the receptor rather than relative to a fixed point in space.