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Article

A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., 117997 Moscow, Russia
2
National Research University Higher School of Economics, 101000 Moscow, Russia
3
Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Campus Vienna BioCenter 5, A-1030 Vienna, Austria
4
Moscow Institute of Physics and Technology (State University), 141701 Dolgoprudny, Russia
*
Author to whom correspondence should be addressed.
Academic Editors: Antonio Rescifina and Giuseppe Floresta
Int. J. Mol. Sci. 2022, 23(16), 9221; https://doi.org/10.3390/ijms23169221
Received: 16 July 2022 / Revised: 13 August 2022 / Accepted: 15 August 2022 / Published: 17 August 2022
(This article belongs to the Collection Feature Papers in Molecular Informatics)
Understanding fusion mechanisms employed by SARS-CoV-2 spike protein entails realistic transmembrane domain (TMD) models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we propose a comprehensive computational framework to model the spike TMD only based on its primary structure. We performed amino acid sequence pattern matching and compared the molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and selected an appropriate template for homology modeling. We then iteratively built a model of spike TMD, adjusting “dynamic MHP portraits” and residue variability motifs. The stability of this model, with and without palmitoyl modifications downstream of the TMD, and several alternative configurations (including a recent NMR structure), was tested in all-atom molecular dynamics simulations in a POPC bilayer mimicking the viral envelope. Our model demonstrated unique stability under the conditions applied and conforms to known basic principles of TM helix packing. The original computational framework looks promising and could potentially be employed in the construction of 3D models of TM trimers for a wide range of membrane proteins. View Full-Text
Keywords: structure prediction; viral fusion protein; molecular dynamics simulation; molecular hydrophobicity potential; transmembrane domain; helical trimer; template-based modeling; Monte Carlo conformational search structure prediction; viral fusion protein; molecular dynamics simulation; molecular hydrophobicity potential; transmembrane domain; helical trimer; template-based modeling; Monte Carlo conformational search
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MDPI and ACS Style

Aliper, E.T.; Krylov, N.A.; Nolde, D.E.; Polyansky, A.A.; Efremov, R.G. A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain. Int. J. Mol. Sci. 2022, 23, 9221. https://doi.org/10.3390/ijms23169221

AMA Style

Aliper ET, Krylov NA, Nolde DE, Polyansky AA, Efremov RG. A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain. International Journal of Molecular Sciences. 2022; 23(16):9221. https://doi.org/10.3390/ijms23169221

Chicago/Turabian Style

Aliper, Elena T., Nikolay A. Krylov, Dmitry E. Nolde, Anton A. Polyansky, and Roman G. Efremov. 2022. "A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain" International Journal of Molecular Sciences 23, no. 16: 9221. https://doi.org/10.3390/ijms23169221

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