Universität zu Köln

Bastys, Tomas, Gapsys, Vytautas ORCID: 0000-0002-6761-7780, Doncheva, Nadezhda T., Kaiser, Rolf, de Groot, Bert L. and Kalinina, Olga V. (2018). Consistent Prediction of Mutation Effect on Drug Binding in HIV-1 Protease Using Alchemical Calculations. J. Chem. Theory Comput., 14 (7). S. 3397 - 3409. WASHINGTON: AMER CHEMICAL SOC. ISSN 1549-9626

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Abstract

Despite a large number of antiretroviral drugs targeting HIV-1 protease for inhibition, mutations in this protein during the course of patient treatment can render them inefficient. This emerging resistance inspired numerous computational studies of the HIV-1 protease aimed at predicting the effect of mutations on drug binding in terms of free binding energy Delta G, as well as in mechanistic terms. In this study, we analyze ten different protease-inhibitor complexes carrying major resistance-associated mutations (RAMs) G48V, I50V, and L90M using molecular dynamics simulations. We demonstrate that alchemical free energy calculations can consistently predict the effect of mutations on drug binding. By explicitly probing different protonation states of the catalytic aspartic dyad, we reveal the importance of the correct choice of protonation state for the accuracy of the result. We also provide insight into how different mutations affect drug binding in their specific ways, with the unifying theme of how all of them affect the crucial drug binding regions of the protease.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bastys, Tomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Gapsys, Vytautas UNSPECIFIED orcid.org/0000-0002-6761-7780 UNSPECIFIED Doncheva, Nadezhda T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaiser, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED de Groot, Bert L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalinina, Olga V. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-181511
DOI:	10.1021/acs.jctc.7b01109
Journal or Publication Title:	J. Chem. Theory Comput.
Volume:	14
Number:	7
Page Range:	S. 3397 - 3409
Date:	2018
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1549-9626
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN-IMMUNODEFICIENCY-VIRUS; FREE-ENERGY CALCULATIONS; MOLECULAR-DYNAMICS SIMULATIONS; CATALYTIC ASPARTYL GROUPS; TYPE-1 PROTEASE; RESISTANT MUTATIONS; PROTONATION STATE; FORCE-FIELD; IN-VIVO; NEUTRON CRYSTALLOGRAPHY Multiple languages Chemistry, Physical; Physics, Atomic, Molecular & Chemical Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18151