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Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution
Nevra Özer1, Ayşegül Özen2, Celia A Schiffer2
1Polymer Research Center and Chemical Engineering Department, Bogazici University Bebek, Istanbul, Turkey.
Evolutionary Applications
|February 17, 2015
Summary
Mutations in HIV-1 protease cause drug resistance by altering substrate recognition. Coevolution with natural substrates restores wild-type function, revealing insights into drug resistance and evolutionary optimization.
Area of Science:
- Structural biology
- Molecular dynamics
- Virology
Background:
- Drug resistance in HIV-1 protease arises from mutations disrupting substrate binding and cleavage.
- Understanding the dynamic interplay between protease mutations and substrate evolution is crucial for combating resistance.
Purpose of the Study:
- To investigate the structural dynamics of mutant HIV-1 proteases in complex with natural substrates.
- To elucidate the mechanisms by which substrate coevolution restores wild-type protease function.
- To understand the role of hinge axes dynamics in drug resistance and evolutionary optimization.
Main Methods:
- Utilized the Anisotropic Network Model (ANM) to analyze the collective dynamics of mutant HIV-1 protease structures.
- Assessed dynamics of proteases bound to p1-p6 and NC-p1 substrates.
- Correlated dynamic behavior with experimental findings on substrate recognition.
Main Results:
- HIV-1 protease mutations perturb critical hinge axes involved in substrate binding and dimerization.
- Substrate coevolution with p1-p6 and NC-p1 substrates restores wild-type dynamic behavior in mutant proteases.
- Dynamic behavior of NC-p1 bound protease variants mirrors proteases bound to other substrates, aligning with experimental data.
- Hinge residue dynamics explain the coevolution of substrates and their interdependent recognition.
Conclusions:
- Structural dynamics provide a basis for understanding HIV-1 protease drug resistance.
- Coevolution of substrates plays a key role in restoring protease function and overcoming drug resistance.
- This study enhances comprehension of the evolutionary optimization processes in the HIV-1 protease system.
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