Effect of Structural Stress on the Flexibility and Adaptability of HIV-1 Protease

• Published in: Journal of chemical information and modeling Vol. 51; no. 5; pp. 1064 - 1073
• Main Authors: Oehme, Daniel P., Wilson, David J. D., Brownlee, Robert T. C.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 23-05-2011
• Subjects: Applied sciences; Binding sites; Biological and medical sciences; Computational Biochemistry; Computer science; control theory; systems; Crystallography, X-Ray; Drug resistance; Drug Resistance, Viral; Exact sciences and technology; General pharmacology; HIV; HIV Protease - chemistry; HIV Protease - genetics; HIV Protease Inhibitors - chemistry; HIV-1 - chemistry; HIV-1 - enzymology; Human immunodeficiency virus; Isoleucine - chemistry; Ligands; Medical sciences; Molecular Docking Simulation; Mutation; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Programming languages; Protease inhibitors; Protein Binding; Protein Conformation; Software; Availability; Drug; Data type; Pharmaceutical technology; HIV-1 virus; Variability; Adaptability; Retroviridae; Pharmacology; Group structure; Lentivirus; Virus; Residue; Human immunodeficiency virus; Structural analysis; Conformation
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci2000677

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.