Universität zu Köln

Bastys, Tomas, Gapsys, Vytautas, Walter, Hauke, Heger, Eva, Doncheva, Nadezhda T., Kaiser, Rolf, de Groot, Bert L. and Kalinina, Olga, V (2020). Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors. Retrovirology, 17 (1). LONDON: BMC. ISSN 1742-4690

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Abstract

Background HIV-1 can develop resistance to antiretroviral drugs, mainly through mutations within the target regions of the drugs. In HIV-1 protease, a majority of resistance-associated mutations that develop in response to therapy with protease inhibitors are found in the protease's active site that serves also as a binding pocket for the protease inhibitors, thus directly impacting the protease-inhibitor interactions. Some resistance-associated mutations, however, are found in more distant regions, and the exact mechanisms how these mutations affect protease-inhibitor interactions are unclear. Furthermore, some of these mutations, e.g. N88S and L76V, do not only induce resistance to the currently administered drugs, but contrarily induce sensitivity towards other drugs. In this study, mutations N88S and L76V, along with three other resistance-associated mutations, M46I, I50L, and I84V, are analysed by means of molecular dynamics simulations to investigate their role in complexes of the protease with different inhibitors and in different background sequence contexts. Results Using these simulations for alchemical calculations to estimate the effects of mutations M46I, I50L, I84V, N88S, and L76V on binding free energies shows they are in general in line with the mutations' effect on IC50 values. For the primary mutation L76V, however, the presence of a background mutation M46I in our analysis influences whether the unfavourable effect of L76V on inhibitor binding is sufficient to outweigh the accompanying reduction in catalytic activity of the protease. Finally, we show that L76V and N88S changes the hydrogen bond stability of these residues with residues D30/K45 and D30/T31/T74, respectively. Conclusions We demonstrate that estimating the effect of both binding pocket and distant mutations on inhibitor binding free energy using alchemical calculations can reproduce their effect on the experimentally measured IC50 values. We show that distant site mutations L76V and N88S affect the hydrogen bond network in the protease's active site, which offers an explanation for the indirect effect of these mutations on inhibitor binding. This work thus provides valuable insights on interplay between primary and background mutations and mechanisms how they affect inhibitor binding.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bastys, Tomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Gapsys, Vytautas UNSPECIFIED UNSPECIFIED UNSPECIFIED Walter, Hauke UNSPECIFIED UNSPECIFIED UNSPECIFIED Heger, Eva UNSPECIFIED UNSPECIFIED 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:38-333429
DOI:	10.1186/s12977-020-00520-6
Journal or Publication Title:	Retrovirology
Volume:	17
Number:	1
Date:	2020
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1742-4690
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VIRUS TYPE-1 PROTEASE; MOLECULAR-DYNAMICS SIMULATIONS; DRUG-RESISTANCE; REVERSE-TRANSCRIPTASE; FREE-ENERGY; CROSS-RESISTANCE; INCREASED SUSCEPTIBILITY; ATAZANAVIR RESISTANCE; NELFINAVIR-RESISTANT; CRYSTAL-STRUCTURES Multiple languages Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33342