BAT2: an Open-Source Tool for Flexible, Automated, and Low Cost Absolute Binding Free Energy Calculations

Overview

Journal J Chem Theory Comput

Publisher American Chemical Society

Specialties Biochemistry
Chemistry

Date 2024 Aug 1

PMID 39088306

Authors

Germano Heinzelmann

David J Huggins

Michael K Gilson

Affiliations

Soon will be listed here.

Abstract

Absolute binding free energy (ABFE) calculations with all-atom molecular dynamics (MD) have the potential to greatly reduce costs in the first stages of drug discovery. Here, we introduce BAT2, the new version of the Binding Affinity Tool (BAT.py), designed to combine full automation of ABFE calculations with high-performance MD simulations, making it a potential tool for virtual screening. We describe and test several changes and new features that were incorporated into the code, such as relative restraints between the protein and the ligand instead of using fixed dummy atoms, support for the OpenMM simulation engine, a merged approach to the application/release of restraints, support for cobinders and proteins with multiple chains, and many others. We also reduced the simulation times for each ABFE calculation, assessing the effect on the expected robustness and accuracy of the calculations.

References

Chen B, Harrison R, Papadatos G, Willett P, Wood D, Lewell X . Evaluation of machine-learning methods for ligand-based virtual screening. J Comput Aided Mol Des. 2007; 21(1-3):53-62. DOI: 10.1007/s10822-006-9096-5. View

Wang L, Martinez T, Pande V . Building Force Fields: An Automatic, Systematic, and Reproducible Approach. J Phys Chem Lett. 2015; 5(11):1885-91. PMC: 9649520. DOI: 10.1021/jz500737m. View

Ohlknecht C, Perthold J, Lier B, Oostenbrink C . Charge-Changing Perturbations and Path Sampling via Classical Molecular Dynamic Simulations of Simple Guest-Host Systems. J Chem Theory Comput. 2020; 16(12):7721-7734. PMC: 7726903. DOI: 10.1021/acs.jctc.0c00719. View

Salomon-Ferrer R, Gotz A, Poole D, Le Grand S, Walker R . Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. J Chem Theory Comput. 2015; 9(9):3878-88. DOI: 10.1021/ct400314y. View

Jakalian A, Jack D, Bayly C . Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J Comput Chem. 2002; 23(16):1623-41. DOI: 10.1002/jcc.10128. View

OBoyle N, Banck M, James C, Morley C, Vandermeersch T, Hutchison G . Open Babel: An open chemical toolbox. J Cheminform. 2011; 3:33. PMC: 3198950. DOI: 10.1186/1758-2946-3-33. View

Konagurthu A, Whisstock J, Stuckey P, Lesk A . MUSTANG: a multiple structural alignment algorithm. Proteins. 2006; 64(3):559-74. DOI: 10.1002/prot.20921. View

Muegge I, Hu Y . Recent Advances in Alchemical Binding Free Energy Calculations for Drug Discovery. ACS Med Chem Lett. 2023; 14(3):244-250. PMC: 10009785. DOI: 10.1021/acsmedchemlett.2c00541. View

Gilson M, Given J, Bush B, McCammon J . The statistical-thermodynamic basis for computation of binding affinities: a critical review. Biophys J. 1997; 72(3):1047-69. PMC: 1184492. DOI: 10.1016/S0006-3495(97)78756-3. View

10.

Lee T, Hu Y, Sherborne B, Guo Z, York D . Toward Fast and Accurate Binding Affinity Prediction with pmemdGTI: An Efficient Implementation of GPU-Accelerated Thermodynamic Integration. J Chem Theory Comput. 2017; 13(7):3077-3084. PMC: 5843186. DOI: 10.1021/acs.jctc.7b00102. View

11.

Izadi S, Anandakrishnan R, Onufriev A . Building Water Models: A Different Approach. J Phys Chem Lett. 2014; 5(21):3863-3871. PMC: 4226301. DOI: 10.1021/jz501780a. View

12.

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

13.

Li P, Song L, Merz Jr K . Systematic Parameterization of Monovalent Ions Employing the Nonbonded Model. J Chem Theory Comput. 2015; 11(4):1645-57. DOI: 10.1021/ct500918t. View

14.

Ferreira L, Dos Santos R, Oliva G, Andricopulo A . Molecular docking and structure-based drug design strategies. Molecules. 2015; 20(7):13384-421. PMC: 6332083. DOI: 10.3390/molecules200713384. View

15.

Eastman P, Pande V . Efficient nonbonded interactions for molecular dynamics on a graphics processing unit. J Comput Chem. 2009; 31(6):1268-72. PMC: 2841709. DOI: 10.1002/jcc.21413. View

16.

Dorr M, Fibinger M, Last D, Schmidt S, Santos-Aberturas J, Bottcher D . Fully automatized high-throughput enzyme library screening using a robotic platform. Biotechnol Bioeng. 2016; 113(7):1421-32. DOI: 10.1002/bit.25925. View

17.

Heinzelmann G, Henriksen N, Gilson M . Attach-Pull-Release Calculations of Ligand Binding and Conformational Changes on the First BRD4 Bromodomain. J Chem Theory Comput. 2017; 13(7):3260-3275. PMC: 5541932. DOI: 10.1021/acs.jctc.7b00275. View

18.

Chen W, Cui D, Jerome S, Michino M, Lenselink E, Huggins D . Enhancing Hit Discovery in Virtual Screening through Absolute Protein-Ligand Binding Free-Energy Calculations. J Chem Inf Model. 2023; 63(10):3171-3185. DOI: 10.1021/acs.jcim.3c00013. View

19.

Torres P, Sodero A, Jofily P, Silva-Jr F . Key Topics in Molecular Docking for Drug Design. Int J Mol Sci. 2019; 20(18). PMC: 6769580. DOI: 10.3390/ijms20184574. View

20.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View