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Updated: May 25, 2026
10:50
Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
Published on: September 15, 2010
Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease
Seema Mittal1, Yufeng Cai, Madhavi N L Nalam
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Journal of the American Chemical Society
|February 3, 2012
Summary
Altering the flexibility of the human immunodeficiency virus Type-1 (HIV-1) protease hydrophobic core significantly impacts its activity. This finding supports how mutations can affect drug resistance by modulating enzyme function.
Area of Science:
- Biochemistry
- Structural Biology
- Virology
Background:
- Human immunodeficiency virus Type-1 (HIV-1) protease is vital for viral maturation.
- Hydrophobic core rearrangement is essential for protease activity and drug resistance.
- Protease flexibility may play a key role in enzyme function.
Purpose of the Study:
- To investigate the role of flexibility in HIV-1 protease activity.
- To determine if altering flexibility impacts enzyme function and drug resistance.
Main Methods:
- Engineered disulfide bonds in flexible regions of HIV-1 protease.
- Confirmed disulfide bond formation using crystal structures, alkylation, and mass spectrometry.
- Assessed enzyme activity in oxidized and reduced states and performed molecular dynamics simulations.
Main Results:
- Disulfide cross-linking drastically reduced protease activity.
- Enzyme activity was restored upon reduction of disulfide bonds.
- Simulations showed altered dynamics propagated from the engineered disulfide bond.
Conclusions:
- Altered flexibility in the hydrophobic core modulates HIV-1 protease activity.
- Distal mutations may confer drug resistance by altering enzyme flexibility and activity balance.
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