Abstract:
HIV-1 protease is a drug target against AIDS and understanding its molecu- lar recognition processes is important in development of drugs. Here, the combined computational methodologies used put three different perspectives together to study the recognition and binding processes in HIV-1 protease complex structures. To inves- tigate the substrate specificity, a biased sequence search threading (BSST) technique is introduced. The potential sequence space is efficiently explored by a low resolu- tion knowledge-based scoring function and potential substrate sequences are predicted, which are correlated with the natural substrates. The change in the molecular recogni- tion events, which lead to drug resistance via mutations and/or co-evolution between protease and substrate, is studied by analyzing the collective dynamics of ligand bound protease structures using the Anisotropic Network Model (ANM). The analysis of the dynamic fluctuations imply that substrate and inhibitor complex structures fall into two groups, which differ by the direction of the fluctuations of some mechanistically crucial sites that determine the main rotational axes in the cooperative modes of motion. The network of key interactions within the protease complex structures is also examined by the communication pathways generated using both topological features reflected by the Gaussian Network Model (GNM) and residue-specific interactions estimated by a modeled van der Waals potential. The hinge regions with minimum fluctuation in the most cooperative modes, i.e. dimerization, active site, flap and substrate cleft regions of the protease, act as messengers in the communication. The short pathways between the substrate and protease active site defines the core regions that either function in ligand recognition or interact with the residues that confer drug resistance as the key interacting regions. Moreover, the examination of structural properties of mutant structures indicates a higher correlation of the wild-type complex with the co-evolved structure than the other mutant structures with respect to both dynamic fluctuations and ensemble of short pathways. Overall, this study adds a further structural and dynamic view to the understanding of the HIV-1 protease system with respect to its interactions to the substrates and drugs, and further to drug resistance.
