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Molecules 2016, 21(4), 499; doi:10.3390/molecules21040499

Calculation of Relative Binding Free Energy in the Water-Filled Active Site of Oligopeptide-Binding Protein A

Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Muthgasse 18, A-1190 Vienna, Austria
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Academic Editor: James W. Gauld
Received: 1 March 2016 / Revised: 30 March 2016 / Accepted: 11 April 2016 / Published: 15 April 2016
(This article belongs to the Special Issue Computational Design: A New Approach to Drug and Molecular Discovery)
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Abstract

The periplasmic oligopeptide binding protein A (OppA) represents a well-known example of water-mediated protein-ligand interactions. Here, we perform free-energy calculations for three different ligands binding to OppA, using a thermodynamic integration approach. The tripeptide ligands share a high structural similarity (all have the sequence KXK), but their experimentally-determined binding free energies differ remarkably. Thermodynamic cycles were constructed for the ligands, and simulations conducted in the bound and (freely solvated) unbound states. In the unbound state, it was observed that the difference in conformational freedom between alanine and glycine leads to a surprisingly slow convergence, despite their chemical similarity. This could be overcome by increasing the softness parameter during alchemical transformations. Discrepancies remained in the bound state however, when comparing independent simulations of the three ligands. These difficulties could be traced to a slow relaxation of the water network within the active site. Fluctuations in the number of water molecules residing in the binding cavity occur mostly on a timescale larger than the simulation time along the alchemical path. After extensive simulations, relative binding free energies that were converged to within thermal noise could be obtained, which agree well with available experimental data. View Full-Text
Keywords: OppA; free-energy calculations; free-energy perturbation; molecular dynamics simulations; computational alchemy; thermodynamic integration; GROMOS OppA; free-energy calculations; free-energy perturbation; molecular dynamics simulations; computational alchemy; thermodynamic integration; GROMOS
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Maurer, M.; de Beer, S.B.A.; Oostenbrink, C. Calculation of Relative Binding Free Energy in the Water-Filled Active Site of Oligopeptide-Binding Protein A. Molecules 2016, 21, 499.

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