Trypsin-Ligand Binding Free Energies from Explicit and Implicit Solvent Simulations with Polarizable Potential

Dian Jiao; Jiajing Zhang; Robert E Duke; Guohui Li; Michael J Schnieders; Pengyu Ren

doi:10.1002/jcc.21268

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Trypsin-Ligand Binding Free Energies from Explicit and Implicit Solvent Simulations with Polarizable Potential

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Trypsin-Ligand Binding Free Energies from Explicit and Implicit Solvent Simulations with Polarizable Potential

Dian Jiao, Jiajing Zhang, Robert E Duke, Guohui Li, Michael J Schnieders and Pengyu Ren

Journal of computational chemistry, Vol.30(11), pp.1701-1711

08/2009

DOI: 10.1002/jcc.21268

PMCID: PMC2752704

PMID: 19399779

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Abstract

We have calculated the binding free energies of a series of benzamidine-like inhibitors to trypsin with a polarizable force field using both explicit and implicit solvent approaches. Free energy perturbation has been performed for the ligands in bulk water and in protein complex with molecular dynamics simulations. The calculated binding free energies are well within the accuracy of experimental measurement and the direction of change is predicted correctly in call cases. We analyzed the molecular dipole moments of the ligands in gas, water and protein environments. Neither binding affinity nor ligand solvation free energy in bulk water shows much dependence on the molecular dipole moments of the ligands. Substitution of the aromatic or the charged group in the ligand results in considerable change in the solvation energy in bulk water and protein whereas the binding affinity varies insignificantly due to cancellation. The effect of chemical modification on ligand charge distribution is mostly local. Replacing benzene with diazine has minimal impact on the atomic multipoles at the amidinium group. We have also utilized an implicit solvent based end-state approach to evaluate the binding free energies of these inhibitors. In this approach, the polarizable multipole model combined with Poisson-Boltzmann/surface area (PMPB/SA) provides the electrostatic interaction energy and the polar solvation free energy. Overall the relative binding free energies obtained from the PMPB/SA model are in good agreement with the experimental data.

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Title: Subtitle: Trypsin-Ligand Binding Free Energies from Explicit and Implicit Solvent Simulations with Polarizable Potential
Creators: Dian Jiao - Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712 USA
Jiajing Zhang - Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712 USA
Robert E Duke - Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA and Laboratory of Structural Biology, National Institute of Environmental Health Sciences-National Institutes of Health, Research Triangle Park, NC 27709 USA
Guohui Li - Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China
Michael J Schnieders - University of Iowa, Roy J. Carver Department of Biomedical Engineering
Pengyu Ren - Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712 USA
Resource Type: Journal article
Publication Details: Journal of computational chemistry, Vol.30(11), pp.1701-1711
DOI: 10.1002/jcc.21268
PMID: 19399779
PMCID: PMC2752704
NLM abbreviation: J Comput Chem
ISSN: 0192-8651
eISSN: 1096-987X
Language: English
Date published: 08/2009
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology
Record Identifier: 9984024504002771

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