What Binds Cationic Photosensitizers Better: Brownian Dynamics Reveals Key Interaction Sites on Spike Proteins of SARS-CoV, MERS-CoV, and SARS-CoV-2.

Vladimir Fedorov,Andrew Rubin,Sergei Khruschev,Ekaterina Kholina,Ilya Kovalenko,Marina Strakhovskaya

doi:10.3390/v13081615

Abstract

We compared the electrostatic properties of the spike proteins (S-proteins) of three coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, and their interactions with photosensitizers (PSs), octacationic octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+) and monocationic methylene blue (MB). We found a major common PS binding site at the connection of the S-protein stalk and head. The molecules of Zn-PcChol8+ and MB also form electrostatic encounter complexes with large area of negative electrostatic potential at the head of the S-protein of SARS-CoV-2, between fusion protein and heptad repeat 1 domain. The top of the SARS-CoV spike head demonstrates a notable area of electrostatic contacts with Zn-PcChol8+ and MB that corresponds to the N-terminal domain. The S-protein protomers of SARS-CoV-2 in “open” and “closed” conformations demonstrate different ability to attract PS molecules. In contrast with Zn-PcChol8+, MB possesses the ability to penetrate inside the pocket formed as a result of SARS-CoV-2 receptor binding domain transition into the “open” state. The existence of binding site for cationic PSs common to the S-proteins of SARS-CoV, SARS-CoV-2, and MERS-CoV creates prospects for the wide use of this type of PSs to combat the spread of coronaviruses.

Highlights

IntroductionBetween April 2012 and December 2019, the Middle East Respiratory Syndrome coronavirus (MERS-CoV) infected 2499 people in 27 countries and 858 people died [3,4]
These three S-proteins have different negative charges, SARS-CoV-2 has the lowest value of −30 elementary charges compared to −48 in SARS-CoV and −50 in MERS-CoV
S-protein stalks of SARS-CoV and SARS-CoV-2 show three large areas of negative electrostatic potential, with the largest negatively charged area located at the stalk and head connection, whereas the MERS-CoV S-protein stalk demonstrates only two major areas of negative potential, one at the stalk and head connection and the other at the cytoplasmic domain

Summary

Introduction

Between April 2012 and December 2019, the Middle East Respiratory Syndrome coronavirus (MERS-CoV) infected 2499 people in 27 countries and 858 people died [3,4]. The Severe Acute Respiratory Syndrome type 2 coronavirus (SARS-CoV-2) caused the COVID-19 pandemic, which has already caused 4,265,903 deaths of 200,840,180 infected (at 9 August 2021) [5] and led to global social problems and economic losses. Epidemic SARS-CoV, MERS-CoV, and pandemic SARS-CoV-2 are all from the Betacoronaviruses genus, the Nidovirales order, the Coronaviridae family. The latter includes spherical enveloped viruses with a diameter of 80 to 120 nm, the genome of which is represented with single-stranded plus-RNA ranging in size from 26.2 to 37.1 kb [6]. In SARS-CoV-2, RNA has a size of 29.9 kb, contains 14 open reading frames, and encodes 27 proteins [7]

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