Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro

Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro Full article

Journal

Communications Biology
ISSN: 2399-3642

Output data

Year: 2023, Volume: 6, Number: 1, Article number : 1193, Pages count : DOI: 10.1038/s42003-023-05584-6

Authors

Agback Tatiana ¹ , Lesovoy Dmitry ^2,3 , Han Xiao ⁴ , Lomzov Alexander ⁵ , Sun Renhua ⁴ , Sandalova Tatyana ⁴ , Orekhov Vladislav Yu. ^6,3 , Achour Adnane ⁴ , Agback Peter ¹

Affiliations

1	Department of Molecular Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
2	Department of Structural Biology, Shemyakin-Ovchinnikov, Institute of Bioorganic Chemistry RAS, Moscow, Russia
3	Swedish NMR Centre, University of Gothenburg, Gothenburg, Sweden
4	Science for Life Laboratory, Department of Medicine, Karolinska Institute, and Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
5	Laboratory of Structural Biology, Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
6	Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden

The dengue protease NS2B/NS3pro has been reported to adopt either an ‘open’ or a ‘closed’ conformation. We have developed a conformational filter that combines NMR with MD simulations to identify conformational ensembles that dominate in solution. Experimental values derived from relaxation parameters for the backbone and methyl side chains were compared with the corresponding back-calculated relaxation parameters of different conformational ensembles obtained from free MD simulations. Our results demonstrate a high prevalence for the ‘closed’ conformational ensemble while the ‘open’ conformation is absent, indicating that the latter conformation is most probably due to crystal contacts. Conversely, conformational ensembles in which the positioning of the co-factor NS2B results in a ‘partially’ open conformation, previously described in both MD simulations and X-ray studies, were identified by our conformational filter. Altogether, we believe that our approach allows for unambiguous identification of true conformational ensembles, an essential step for reliable drug discovery

Agback T. , Lesovoy D. , Han X. , Lomzov A. , Sun R. , Sandalova T. , Orekhov V.Y. , Achour A. , Agback P.
Combined NMR and molecular dynamics conformational filter identifies unambiguously dynamic ensembles of Dengue protease NS2B/NS3pro
Communications Biology. 2023. V.6. N1. 1193 . DOI: 10.1038/s42003-023-05584-6 WOS Scopus PMID OpenAlex

Published print:

Nov 24, 2023

Web of science:	WOS:001109195000007
Scopus:	2-s2.0-85177800293
PMID:	38001280
OpenAlex:	W4388978382

DB	Citing
OpenAlex	5
Scopus	2
Web of science	6