title: Effect of structural stress on the flexibility and adaptability of HIV-1 protease.
abstract: Resistance remains a major issue with regards to HIV-1 protease, despite the availability of numerous HIV-1 protease inhibitors and copious amounts of structural and binding data. In an effort to improve our understanding of how HIV-1 protease is able to "outsmart" new drugs, we have investigated the flexibility of HIV-1 protease and in particular how it adapts to different structural stresses. Our analysis has highlighted the effects of space group on the variability between structures of HIV-1 protease and suggests that consideration of multiple structures and appropriate consideration of different conformations of the Ile50 residue is necessary in any structural analysis. Calculation of the root-mean-square deviation on a per-residue basis has been used to identify 'natural variation', while mutational and ligand analyses have been carried out to identify the effect on structure as a result of specific stresses. It was observed that mutations readily cause changes to occur at sites both close to and distant from a mutation site, with changes more likely to occur at residues that are sites of other major mutations. It is also revealed that HIV-1 protease adaption is dependent on the type and the structure of any bound ligand. Identification of the specific changes that occur due to these stresses will aid in the understanding of resistance and also aid in the design of new drugs.
authors.affiliation: Department of Chemistry and La Trobe Institute for Molecular Sciences (LIMS), La Trobe University , Bundoora, Victoria, 3086, Australia.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Oehme
authors.forename: David J D
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Robert T C
authors.initials: RT
authors.lastname: Brownlee
mesh_terms: D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry* / Q000201:enzymology; D007532:Isoleucine / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D007532:Isoleucine; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1