BIOPHYSICAL THEORY AND MODELING |
A Quantum Mechanics/Molecular Mechanic Study of the Wild-Type and N155S Mutant HIV-1 Integrase Complexed with a Diketo Acid
Claudio Nahum Alves 1*, Sergio Marti 2, Raquel Castillo 3, Juan Andres 3, Iñaki Tunon 4, Vicent Moliner 3 and Estanislao Silla 4
1 Universidade Federal do Para
2 Universidad Jaume I
3 UJI
4 UV
* To whom correspondence should be addressed. E-mail: nahum{at}uji.es.
Submitted on February 26, 2007
Revised on March 26, 2007
Accepted on 17 August 2007
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Abstract |
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Integrase (IN) is one of the three human immunodeficiency virus type 1 (HIV-1) enzymes essential for effective viral replication. Recently, mutation studies have been reported and showed that certain degree of viral resistance to Diketo acids (DKAs) appears when some amino-acid residues of integrase active site are mutated. Mutations represent a fascinating experimental challenge and theoretical simulations are invited to disclose still unexplored features of enzyme reactions. The aim of this work is to understand molecular mechanisms of HIV-1 IN drug resistance, which will be useful for designing anti-HIV inhibitors with unique resistance profiles. In this study, we use molecular dynamics simulations, within the hybrid Quantum Mechanics / Molecular Mechanics (QM/MM) approach, to determine the protein-ligand interaction energy for wild-type and N155S mutant HIV-1 IN, both complexed with a diketo acid. This hybrid methodology has the advantage of the inclusion of quantum effects such as ligand polarization upon binding, which can be very important when highly polarizable groups are embedded in anisotropic environments, as for example in metal-containing active sites. Furthermore, an energy terms decomposition analysis has been performed to determine contributions of individual residues to the enzyme-inhibitor interactions. The results reveal that there is a strong interaction between the Lys159, Lys156, Asn155 residues and Mg2+ cation and the diketo acid inhibitor. Our calculations show that the binding energy is higher in wild-type than in N155S mutant, in accordance with the experimental results. The role of the mutated residue has been thus checked as 2 maintaining the structure of the ternary complex formed by the protein, the Mg2+ cation and the inhibitor. These results might be useful to design compounds with more interesting anti-HIV-1 IN activity on the basis of its three-dimensional structure.
Key Words:
B3LYP/MM, Diketo acids, HIV-1 IN, ab initio, molecular dynamics (MD), quantum mechanical/molecular mechanical (QM/MM)
