Analyzing Electrostatic Determinants of Affinity and Promiscuity in the HIV-1 Reverse Transcriptase System Using Charge Optimization

Abstract

Electrostatic charge optimization (Lee and Tidor, J. Chem. Phys. 1997) was used to study the binding site of wild type and mutant HIV-1 reverse transcriptase (RT) complexed with the non-nucleoside inhibitors nevirapine and rilpivirine (TMC-278). Our ultimate goal is to analyze and to further understand the electrostatic determinants of tight binding and broad molecular recognition toward this rapidly-mutating target. For each inhibitor-RT mutant pair, we computed the drug's optimal charge distribution - the hypothetical charge distribution that would bind to the target variant more tightly than any other isosteric drug. By comparing these optimal charge distributions with each drug's actual charge distribution, we are able to identify potential sites of electrostatic noncomplementarity that may be altered to increase binding affinity. Additionally, by comparing the electrostatic optima for a given drug toward multiple RT variants, we can gain insight into the sensitivity of the electrostatic determinants of binding to the variability in RT as a result of certain drug resistance mutations.