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@article{561245, author = {Lepšík, Martin and Kříž, Zdeněk and Havlas, Zdeněk}, article_number = {2}, keywords = {HIV; inhibitor; mutation; drug design; AMBER; MM-GBSA; energy decomposition; hydrogen bond; entropy calculation}, language = {eng}, issn = {0887-3585}, journal = {Proteins: Structure, Function, and Bioinformatics}, title = {Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations}, url = {http://www3.interscience.wiley.com/cgi-bin/abstract/109075287/ABSTRACT}, volume = {57}, year = {2004} }
TY - JOUR ID - 561245 AU - Lepšík, Martin - Kříž, Zdeněk - Havlas, Zdeněk PY - 2004 TI - Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations JF - Proteins: Structure, Function, and Bioinformatics VL - 57 IS - 2 SP - 279-293 EP - 279-293 PB - Wiley SN - 08873585 KW - HIV KW - inhibitor KW - mutation KW - drug design KW - AMBER KW - MM-GBSA KW - energy decomposition KW - hydrogen bond KW - entropy calculation UR - http://www3.interscience.wiley.com/cgi-bin/abstract/109075287/ABSTRACT N2 - A subnanomolar inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, designated QF34, potently inhibits the wild-type 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. ER -
LEPŠÍK, Martin, Zdeněk KŘÍŽ and Zdeněk HAVLAS. Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations. \textit{Proteins: Structure, Function, and Bioinformatics}. Wiley, 2004, vol.~57, No~2, p.~279-293. ISSN~0887-3585.
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