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Calculation of binding free energies of inhibitors to plasmepsin II
Author(s) -
Steiner Denise,
Oostenbrink Chris,
Diederich François,
Zürcher Martina,
van Gunsteren Wilfred F.
Publication year - 2011
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.21761
Subject(s) - replica , thermodynamic integration , hamiltonian (control theory) , chemistry , molecular dynamics , computational chemistry , ligand (biochemistry) , bound state , binding energy , thermodynamics , statistical physics , entropy (arrow of time) , physics , quantum mechanics , mathematics , art , mathematical optimization , biochemistry , receptor , visual arts
An understanding at the atomic level of the driving forces of inhibitor binding to the protein plasmepsin (PM) II would be of interest to the development of drugs against malaria. To this end, three state of the art computational techniques to compute relative free energies—thermodynamic integration (TI), Hamiltonian replica‐exchange (H‐RE) TI, and comparison of bound versus unbound ligand energy and entropy—were applied to a protein‐ligand system of PM II and several exo ‐3‐amino‐7‐azabicyclo[2.2.1]heptanes and the resulting relative free energies were compared with values derived from experimental IC 50 values. For this large and flexible protein‐ligand system, the simulations could not properly sample the relevant parts of the conformational space of the bound ligand, resulting in failure to reproduce the experimental data. Yet, the use of Hamiltonian replica exchange in conjunction with thermodynamic integration resulted in enhanced convergence and computational efficiency compared to standard thermodynamic integration calculations. The more approximate method of calculating only energetic and entropic contributions of the ligand in its bound and unbound states from conventional molecular dynamics (MD) simulations reproduced the major trends in the experimental binding free energies, which could be rationalized in terms of energetic and entropic characteristics of the different structural and physico‐chemical properties of the protein and ligands. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011