role of ligand reorganization and conformational restraints on the binding free energies of dapy non-nucleoside inhibitors to hiv reverse transcriptase配体的重组和构象限制绑定dapy自由能量的非核苷逆转录酶抑制剂艾滋病毒.pdf

Computational Molecular Bioscience, 2012, 2, 7-22 /10.4236/cmb.2012.21002 Published Online March 2012 (http://www.SciRP.org/journal/cmb) Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase Emilio Gallicchio BioMaPS Institute for Quantitative Biology, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, USA Email: emilio@ Received January 28, 2012; revised February 21, 2012; accepted March 2, 2012 ABSTRACT The results of computer simulations of the binding of etravirine (TMC125) and rilpivirine (TMC278) to HIV reverse transcriptase are reported. It is confirmed that consistent binding free energy estimates are obtained with or without the application of torsional restraints when the free energies of imposing the restraints are taken into account. The restraints have a smaller influence on the thermodynamics and apparent kinetics of binding of TMC125 compared to the more flexible TMC278 inhibitor. The concept of the reorganization free energy of binding is useful to understand and catego- rize these effects. Contrary to expectations, the use of conformational restraints did not consistently enhance conver- gence of binding free energy estimates due to suppression of binding/unbinding pathways and due to the influence of rotational degrees of freedom not directly controlled by the restraints. Physical insights concerning the thermodynamic driving forces for binding and the role of “jiggling” and “wiggling” motion of the ligands are discussed. Based on these insights we conclude that an ideal inhibitor, if chemically realizable, would possess the electrostatic charge distribution of