Title

Modulation of HIV protease flexibility by the T80N mutation

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

11-1-2015

Document Type

Article

Disciplines

Biochemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Virology

Abstract

The flexibility of HIV protease (HIVp) plays a critical role in enabling enzymatic activity and is required for substrate access to the active site. While the importance of flexibility in the flaps that cover the active site is well known, flexibility in other parts of the enzyme is also critical for function. One key region is a loop containing Thr 80, which forms the walls of the active site. Although not situated within the active site, amino acid Thr80 is absolutely conserved. The mutation T80N preserves the structure of the enzyme but catalytic activity is completely lost. To investigate the potential influence of the T80N mutation on HIVp flexibility, wide-angle X-ray scattering (WAXS) data was measured for a series of HIVp variants. Starting with a calculated WAXS pattern from a rigid atomic model, the modulations in the intensity distribution caused by structural fluctuations in the protein were predicted by simple analytic methods and compared with the experimental data. An analysis of T80N WAXS data shows that this variant is significantly more rigid than the WT across all length scales. The effects of this single point mutation extend throughout the protein, to alter the mobility of amino acids in the enzymatic core. These results support the contentions that significant protein flexibility extends throughout HIVp and is critical to catalytic function.

Keywords

molecular dynamics simulation, protein flexibility, x-ray solution scattering

DOI of Published Version

10.1002/prot.24737

Source

Proteins. 2015 Nov;83(11):1929-39. doi: 10.1002/prot.24737. Epub 2015 Sep 29. Link to article on publisher's site

Journal/Book/Conference Title

Proteins

Related Resources

Link to Article in PubMed

PubMed ID

25488402

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