Comparing the Performance of Different AMBER Protein Forcefields, Partial Charge Assignments, and Water Models for Absolute Binding Free Energy Calculations

Identifying chemical starting points is a vital first step in small molecule drug discovery and can take significant time and money. For this reason, computational approaches to virtual screening are of great interest as they can lower the cost and shorten timeframes. However, simple approaches such...

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Bibliographic Details
Published in:Journal of chemical theory and computation 2022-04, Vol.18 (4), p.2616-2630
Main Author: Huggins, David J
Format: Article
Language:English
Subjects:
Accuracy
Benchmarks
Binding
Biomolecular Systems
Entropy
Fluid dynamics
Free energy
Ligands
Molecular docking
Molecular Docking Simulation
Molecular Dynamics Simulation
Nuclear Proteins
Parameter identification
Physical simulation
Protein Binding
Proteins
Screening
Test sets
Thermodynamics
Transcription Factors
Water - chemistry
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Summary:Identifying chemical starting points is a vital first step in small molecule drug discovery and can take significant time and money. For this reason, computational approaches to virtual screening are of great interest as they can lower the cost and shorten timeframes. However, simple approaches such as molecular docking and pharmacophore screening are of limited accuracy and provide a low probability of success. Alchemical binding free energies represent a promising approach for virtual screening as they naturally incorporate the key effects of water molecules, protein flexibility, and binding entropy. However, the calculations are technically very challenging, with performance depending on the specific forcefield used. For this reason, it is important that the community has access to benchmark test sets to assess prediction accuracy. In this paper, we present an approach to alchemical binding free energies using OpenMM. We identify effective simulation parameters using an existing BRD4(1) test set and present two new benchmark sets (cMET and PDE2A) that can be used in the community for validation purposes. Our findings also highlight the effectiveness of some AMBER forcefields, in particular, AMBER ff15ipq.
ISSN:1549-9618
1549-9626
DOI:10.1021/acs.jctc.1c01208