M. Lepsik, Z. Kriz, Z. Havlas
Center for Complex Molecular Systems and Biomolecules,
Institute of Organic Chemistry & Biochemistry, Prague, Czech Rep.
Lepsik M, Kriz Z, Havlas Z
Efficiency of a second-generation HIV-1
protease inhibitor studied by molecular dynamics and calculations of
absolute binding free energies.
A subnanomolar inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, designated QF34, potently inhibits the wildtype and drug-resistant enzyme. To explain its broad activity, the binding of QF34 to the wild-type HIV-1 protease is investigated by molecular dynamics simulations and compared to the binding of two inhibitors that are used clinically, saquinavir (SQV) and indinavir (IDV). Analysis of the flexibility of protease residues and inhibitor segments in the complex reveals that segments of QF34 were more mobile during the dynamics studies than the segments of SQV and IDV. The dynamics of hydrogen bonding show that QF34 forms a larger number of stable hydrogen bonds than the two inhibitors that are used clinically. Absolute binding free energies were calculated with molecular mechanics-generalized Born surface area (MM-GBSA) methodology using three protocols. The most consistent results were obtained using the single-trajectory approach, due to cancellation of errors and inadequate sampling in the separate-trajectory protocols. For all three inhibitors, energy components in favor of binding include van der Waals and electrostatic terms, whereas polar solvation and entropy terms oppose binding. Decomposition of binding energies reveals that more protease residues contribute significantly to the binding of QF34 than to the binding of SQV and IDV. Moreover, contributions from protease main chains and side chains are balanced in the case of QF34 (52:48 ratio, respectively), whereas side chain contributions prevail in both SQV and IDV (main-chain:side-chain ratios of 41:59 and 45:55, respectively). The presented results help explain the ability of QF34 to inhibit multiple resistant mutants and should be considered in the design of broad-specificity second-generation HIV-1 protease inhibitors.
two clinically used HIV protease inhibitors, saquinavir (SQV) and
indinavir (IDV). The parameters were taken from gaff force field for use with parm99
AMBER protein force field. Crystal geometries of PR-bound inhibitors
were used. Single conformation fitting to HF/6-31G* ESP was applied.
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Wed Oct 5 09:32:29 BST 2005