Modeling the structure of SARS 3a transmembrane protein using a minimum unfavorable contact approach

Abstract

3a is an accessory protein from SARS coronavirus that is known to play a significant role in the proliferation of the virus by forming tetrameric ion channels. Although the monomeric units are known to consist of three transmembrane (TM) domains, there are no solved structures available for the complete monomer. The present study proposes a structural model for the transmembrane region of the monomer by employing our previously tested approach, which predicts potential orientations of TM α-helices by minimizing the unfavorable contact surfaces between the different TM domains. The best model structure comprising all three α-helices has been subjected to MD simulations to examine its quality. The TM bundle was found to form a compact and stable structure with significant intermolecular interactions. The structural features of the proposed model of 3a account for observations from previous experimental investigations on the activity of the protein. Further analysis indicates that residues from the TM2 and TM3 domains are likely to line the pore of the ion channel, which is in good agreement with a recent experimental study. In the absence of an experimental structure for the protein, the proposed structure can serve as a useful model for inferring structure-function relationships about the protein.

SARS-CoV-2 ORF3a drives dynamic dense body formation for optimal viral infectivity

“…CoV2 is critical for 3DB formation 3a CoV2 and 3a CoV1 share a similar domain structure: an N-terminal region (N-term), a transmembrane-domain region (TMD) and a C-terminal region (C-term) 14,41 , with ~72% amino acid (aa) identity (Fig. 3a).…”

Urea-aromatic interactions in biology

“…Unlike water-soluble proteins, hydrophobic residues of membrane proteins are exposed towards the membrane instead of being buried in the protein interior. Conversely, hydrophilic residues can reside on the protein surface, outside the membrane, neighboring the lipid headgroups, even sometimes, in the protein interior, for example, while forming a channel (Harris and Booth 2012;Ramakrishna et al 2015;Padhi et al 2015). Recent advances in experimental structural biology and computer simulation methodologies have facilitated our understanding on the structural and functional bases of membrane channels at atomic resolution.…”

Cooperation of Hydrophobic Gating, Knock-on Effect, and Ion Binding Determines Ion Selectivity in the p7 Channel

“…NMR studies on the monomeric form have shown that the protein is predominantly α-helical, with two transmembrane segments being connected by a loop. − Due to the difficulty in obtaining transmembrane protein structure, several computational methodologies have been proposed. − There have been a number of attempts to computationally model the oligomeric structure of the p7 protein. − The first complete oligomeric structure was reported in an electron microscopy study, which revealed a flower-shaped structure of the channel . Such a shape of the channel was later confirmed in an NMR study, which showed a hexamer with a funnel-shaped pore. , Each monomeric unit possesses three α-helices, and the different monomeric units are intertwined with one another.…”