Structure and dynamics of the SARS-CoV-2 envelope protein monomer

Abstract

Coronaviruses, especially SARS-CoV-2, present an ongoing threat for human wellbeing. Consequently, elucidation of molecular determinants of their function and interaction with host is an important task. Whereas some of the coronaviral proteins are extensively characterized, others remain understudied. Here, we use molecular dynamics simulations to analyze the structure and dynamics of the SARS-CoV-2 envelope protein (E protein, a viroporin) in the monomeric form. The protein consists of three parts: hydrophobic α-helical transmembrane domain (TMD) and amphiphilic α-helices H2 and H3, which are connected by flexible linkers. We show that TMD is tilted in the membrane, with phenylalanines Phe20, Phe23 and Phe26 facing the lumen. H2 and H3 reside at the membrane surface. Orientation of H2 is not affected by glycosylation, but strongly influenced by palmitoylation pattern of cysteines Cys40, Cys43 and Cys44. On the other hand, glycosylation affects the orientation of H3 and prevents its stacking with H2. We also find that the E protein both generates and senses the membrane curvature, preferably localizing with the cytoplasmic part at the convex regions of the membrane. Curvature sensing may be favorable for assembly of the E protein oligomers, whereas induction of curvature may facilitate budding of the viral particles. The presented results may be helpful for better understanding of the function of coronaviral E protein and viroporins in general, and for overcoming the ongoing SARS-CoV-2 pandemic.

Probing effects of the SARS-CoV-2 E protein on membrane curvature and intracellular calcium

“…Even this model was stable only on the hundreds-of-nanoseconds time scale, and was not evidently permeable to Ca 2+ . Although several articles and preprints in the past year (Borkotoky & Banerjee, 2020; Cao et al, 2020; Gadhave et al, 2020; Gentile et al, 2020; Gupta et al, 2020; Kuzmin et al, 2021; Yu et al, 2021) have reported simulations of this structure, a review of their results shows similar limitations, with abbreviated timescales (Borkotoky & Banerjee, 2020; Gentile et al, 2020; Gupta et al, 2020), reliance on secondary-structure restraints (Cao et al, 2020), elevated RMSDs (Borkotoky & Banerjee, 2020; Cao et al, 2020), and/or dewetting in the absence of electric fields (Cao et al, 2020). Instability of the open structure may reflect underdetermination of the starting protein or membrane models, unresolved interactions with the C-terminal or other domains, or other factors yet to be identified.…”

“…Even this model was stable only on the hundreds-of-nanoseconds time scale, and was not evidently permeable to Ca 2+ . Although several articles and preprints in the past year 74,[79][80][81][82][83][84] have reported simulations of this structure, a review of their results shows similar limitations, with abbreviated timescales, [80][81][82] reliance on secondary-structure restraints, 74 elevated RMSDs, 74,80 and/or dewetting in the absence of electric fields. 74 Instability of the open structure may reflect underdetermination of the starting protein or membrane models, unresolved interactions with the C-terminal or other domains, or other factors yet to be identified.…”

How much energy is stored in SARS‐CoV‐2 and its structural elements?

“…The ERGIC membrane may consist of 55% phosphatidylcholine (PC), 25% phosphatidylethanolamine (PE), 10% phosphatidylinositol (PI), 5% phosphatidylserine (PS), and 5% sphingomyelin (SM) and, its Chol (Cholesterol)/PS molar ratio may be approximately 3.5. 16 , 17 , 18 , 19 , 20 This membrane is made of lipid bilayers with a monolayer separation of 3.6 nm (thickness d = 7.2 nm), after assembly of the virus, has a nearly spherical shape with a diameter of approximately 90 nm (radius r = 45 nm) and referred to as the viral envelope. 17 , 21 Within the viral envelope, approximately 30‐kb long (+) ssRNA and viral ribonucleoprotein (vRNP) complexes are located.…”

Molecular interactions of the M and E integral membrane proteins of SARS-CoV-2

“…It is clear that the protein-lipid interplay around the E-channel is very complex. An additional homology model 14 has been proposed since the start of our study, simulations of an E monomer to characterize the orientation of the helices in the sequence, 57 an experimental structure for the TMs (7K3G). 11 It remains to be determined if the preferred E channel conformation resembles the Korkin model, or if a conformation like the one proposed by the Feig model is biologically relevant at a given stage of the viral life cycle.…”