Resistance mechanism of human immunodeficiency virus type-1 protease to inhibitors: A molecular dynamic approach

Abstract

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors comprise an important class of drugs used in HIV treatments. However, mutations of protease genes accelerated by low fidelity of reverse transcriptase yield drug resistant mutants of reduced affinities for the inhibitors. This problem is considered to be a serious barrier against HIV treatment for the foreseeable future. In this study, molecular dynamic simulation method was used to examine the combinational and additive effects of all known mutations involved in drug resistance against FDA approved inhibitors. Results showed that drug resistant mutations are not randomly distributed along the protease sequence; instead, they are localized on flexible or hot points of the protein chain. Substitution of more hydrophobic residues in flexible points of protease chains tends to increase the folding, lower the flexibility and decrease the active site area of the protease. The reduced affinities of HIV-1 protease for inhibitors seemed to be due to substantial decrease in the size of the active site and flap mobility. A correlation was found between the binding energy of inhibitors and their affinities for each mutant suggesting the distortion of the active site geometry in drug resistance by preventing effective fitting of inhibitors into the enzymes' active site. To overcome the problem of drug resistance of HIV-1 protease, designing inhibitors of variable functional groups and configurations is proposed.

Keywords: AIDS Treatment; Drug Resistance; HIV-1 Protease; Inhibitors.

Figure 1

Curve a: counts of mutations found along protein chains that calculated from all available sequences in PDB data bank (http://www.rcsb.org/pdb). Curve b: RMSF curve for wild-type protease obtained from 20ns simulation at 37°C, 1 atmosphere of pressure, pH7 and in SPCE water box

Figure 2

Curve of RMSD for wild-type and drug resistant mutants extracted from simulations experiments for 20ns period at 37°C, 1 atmosphere of pressure, pH7 and in SPCE water box

Figure 3

Plots of distances between beta carbons of Asp²⁵ from one chain to alpha carbon of Ile⁵⁰ of the same chain during simulation for 20ns simulation at 37°C, 1 atmosphere of pressure, pH7 and in SPCE water box

Figure 4

Plot of RMSF (Average±SE) of protease flaps (residues 42-52) for wild-type and resistant mutants protease extracted from simulation trajectory for 20ns period at 37°C, 1 atmosphere of pressure, pH7 and in SPCE water box

Figure 5

Plot of gyration radius for wild-type and drug resistant mutants with time obtained from 20ns simulation at 37°C, 1 atmosphere of pressure, pH7 and in SPCE water box. The curve is calculated as average from triple experiments

Figure 6

Percent of decrease in the distance between alpha carbon of Asp²⁵ from chain A and alpha carbon of Asp²⁵ from chain B obtained from simulation for 20ns period at 37°C, 1 atmosphere of pressure, pH7 and in SPCE water box.

Figure 7

Schematic representation of HIV-1 protease tertiary structures for wild-type (yellow) and mutant of TRM (red) extracted from the last frame of trajectories for 20ns simulations at 37°C, pH7, 1 atmosphere of pressure and in explicit water box