title: Structural dynamics of native and V260E mutant C-terminal domain of HIV-1 integrase.
abstract: The C-terminal domain (CTD) of HIV-1 integrase is a five stranded β-barrel resembling an SH3 fold. Mutational studies on isolated CTD and full-length IN have reported V260E mutant as either homo-dimerization defective or affecting the stability and folding of CTD. In this study, molecular dynamics simulation techniques were used to unveil the effect of V260E mutation on isolated CTD monomer and dimer. Both monomeric and dimeric forms of wild type and V260E mutant are highly stable during the simulated period. However, the stabilizing π-stacking interaction between Trp243 and Trp243' at the dimer interface is highly disturbed in CTD-V260E (>6 Å apart). The loss in entropy for dimerization is -30 and -25 kcal/mol for CTD-wt and CTD-V260E respectively signifying a weak hydrophobic interaction and its perturbation in CTD-V260E. The mutant Glu260 exhibits strong attraction/repulsion with all the basic/acidic residues of CTD. In addition to this, the dynamics of CTD-wild type and V260E monomers at 498 K was analyzed to elucidate the effect of V260E mutation on CTD folding. Increase in SASA and reduction in the number of contacts in CTD-V260E during simulation highlights the instability caused by the mutation. In general, V260E mutation affects both multimerization and protein folding with a pronounced effect on protein folding rather than multimerization. This study emphasizes the importance of the hydrophobic nature and SH3 fold of CTD in proper functioning of HIV integrase and perturbing this nature would be a rational approach toward designing more selective and potent allosteric anti-HIV inhibitors.
authors.affiliation: Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, 605014, India.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Sangeetha
authors.forename: Rajagopalan
authors.initials: R
authors.lastname: Muthukumaran
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Amutha
mesh_terms: D000595:Amino Acid Sequence; D015658:HIV Infections / Q000821:virology*; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017354:Point Mutation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D058767:Protein Unfolding; D013816:Thermodynamics
chemical_list: D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1