BIOPHYSICAL THEORY AND MODELING |
Insights into saquinavir resistance in the G48V HIV-1 protease: quantum calculations and molecular dynamic simulations
Kitiyaporn Wittayanarakul 1, Ornjira Aruksakunwong 1, Suwipa Saen-oon 1, Wasun Chantratita 2, Vudhichai Parasuk 1, Pornthep Sompornpisut 1* and Supot Hannongbua 1
1 Chulalongkorn University
2 Mahidol University
* To whom correspondence should be addressed. E-mail: pornthep.s{at}chula.ac.th.
Submitted on May 18, 2004
Revised on June 22, 2004
Accepted on 26 October 2004
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Abstract |
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The spread of the acquired immune deficiency syndrome (AIDS) has increasingly become great concern owing largely to the failure of chemotherapies. The G48V is considered the key signature residue mutation of HIV-1 protease developing with saquinavir (SQV) therapy. Molecular dynamics (MD) simulations of the wild-type (wt) and the G48V HIV-1 protease complexed with SQV were carried out to explore structure and interactions of the drug resistance. The MD results combined with the quantum-based and MM/PBSA calculations indicated a monoprotonation took place on D25. The inhibitor binding of the triad residues and its interaction energy in the mutant was similar to those in the wt. The overall structure of both complexes is almost identical. However, the steric conflict of the substituted valine results in the conformational change of the P2 subsite and the disruption of hydrogen bonding between the -NH of the P2 subsite and the backbone -CO of the mutated residue. The magnitude of interaction energy changes was comparable to the experimental Ki data. The designing for a new drug should consider a reduction of steric repulsion on P2 to enhance the activity toward this mutant strain.
Key Words:
G48V, HIV-1 protease, Molecular Dynamics simulations, protonation state, quantum chemical calculations, saquinavir resistance
