Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations

LEPŠÍK, Martin, Zdeněk KŘÍŽ a Zdeněk HAVLAS. Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations. Proteins: Structure, Function, and Bioinformatics. Wiley, 2004, roč. 57, č. 2, s. 279-293. ISSN 0887-3585.

Základní údaje

• Originální název: Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations
• Název česky: Účinnost druhé generace inhibitorů HIV-1 studovaná pomocí molekulové dynamiky a výpočet hodnot vazebné volné energie
• Autoři: LEPŠÍK, Martin (203 Česká republika), Zdeněk KŘÍŽ (203 Česká republika, garant) a Zdeněk HAVLAS (203 Česká republika).
• Vydání: Proteins: Structure, Function, and Bioinformatics, Wiley, 2004, 0887-3585.

Další údaje

• Originální jazyk: angličtina
• Typ výsledku: Článek v odborném periodiku
• Obor: 10403 Physical chemistry
• Stát vydavatele: Česká republika
• Utajení: není předmětem státního či obchodního tajemství
• WWW: URL
• Impakt faktor: Impact factor: 4.429
• Kód RIV: RIV/00216224:14310/04:00010513
• Organizační jednotka: Přírodovědecká fakulta
• UT WoS: 000223926200005
• Klíčová slova anglicky: HIV; inhibitor; mutation; drug design; AMBER; MM-GBSA; energy decomposition; hydrogen bond; entropy calculation
• Štítky: AMBER, drug design, energy decomposition, entropy calculation, HIV, hydrogen bond, inhibitor, MM-GBSA, Mutation

Anotace

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.

Anotace česky

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.

Návaznosti

• LN00A016, projekt VaV: Název: BIOMOLEKULÁRNÍ CENTRUM

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Biomolekulární centrum