e-journal

Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution

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Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type functioning in mutant HIV-1 proteases with coevolution of the natural substrates is provided. The collective dynamics of mutant structures of the protease bound to p1-p6 and NC-p1 substrates are assessed using the Anisotropic Network Model (ANM). The drug-induced protease mutations perturb the mechanistically crucial hinge axes that involve key sites for substrate binding and dimerization and mainly coordinate the intrinsic dynamics. Yet with substrate coevolution, while the wild-type dynamic behavior is restored in both p1-p6 (LP10Fp1-p6D30N/N88D) and NC-p1 (AP2VNC-p1V82A) bound proteases, the dynamic behavior of the NC-p1 bound protease variants (NC-p1V82A and AP2VNC-p1V82A) rather resemble those of the proteases bound to the other substrates, which is consistent with experimental studies. The orientational variations of residue fluctuations along the hinge axes in mutant structures justify the existence of coevolution in p1-p6 and NC-p1 substrates, that is,the dynamic behavior of hinge residues should contribute to the interdependent nature of substrate recognition. Overall, this study aids in the understanding of the structural dynamics basis of drug resistance and evolutionary optimization in the HIV-1 protease system.

Keywords
coevolution, elastic network model,fluctuations, HIV-1 protease.

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Informasi Detail

Judul Seri

Evolutionary Applications

No. Panggil

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Penerbit

: The Authors., 2015

Deskripsi Fisik

Evolutionary Applications 8 (2015) 185–198

Bahasa

English

ISBN/ISSN

doi:10.1111/eva.1224

Klasifikasi

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Tipe Isi

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Tipe Media

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Tipe Pembawa

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Edisi

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Subjek

Agriculture

Info Detail Spesifik

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Pernyataan Tanggungjawab

Wati/Agus

Versi lain/terkait

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