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Comparative molecular dynamics simulations of HIV‐1 integrase and the T66I/M154I mutant: Binding modes and drug resistance to a diketo acid inhibitor
Author(s) -
Brigo Alessandro,
Lee Keun Woo,
Fogolari Federico,
Mustata Gabriela Iurcu,
Briggs James M.
Publication year - 2005
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20447
Subject(s) - molecular dynamics , active site , docking (animal) , integrase , mutant , chemistry , stereochemistry , binding site , human immunodeficiency virus (hiv) , molecule , binding pocket , enzyme , computational chemistry , biochemistry , biology , gene , virology , medicine , nursing , organic chemistry
HIV‐1 IN is an essential enzyme for viral replication and an interesting target for the design of new pharmaceuticals for use in multidrug therapy of AIDS. L‐731,988 is one of the most active molecules of the class of β‐diketo acids. Individual and combined mutations of HIV‐1 IN at residues T66, S153, and M154 confer important degrees of resistance to one or more inhibitors belonging to this class. In an effort to understand the molecular mechanism of the resistance of T66I/M154I IN to the inhibitor L‐731,988 and its specific binding modes, we have carried out docking studies, explicit solvent MD simulations, and binding free energy calculations. The inhibitor was docked against different protein conformations chosen from prior MD trajectories, resulting in 2 major orientations within the active site. MD simulations have been carried out for the T66I/M154I DM IN, DM IN in complex with L‐731,988 in 2 different orientations, and 1QS4 IN in complex with L‐731,988. The results of these simulations show a similar dynamical behavior between T66I/M154I IN alone and in complex with L‐731,988, while significant differences are observed in the mobility of the IN catalytic loop (residues 138–149). Water molecules bridging the inhibitor to residues from the active site have been identified, and residue Gln62 has been found to play an important role in the interactions between the inhibitor and the protein. This work provides information about the binding modes of L‐731,988, as well as insight into the mechanism of inhibitor–resistance in HIV‐1 integrase. Proteins 2005. © 2005 Wiley‐Liss, Inc.