Structure and functional dynamics characterization of the ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domain by combining molecular dynamics with excited normal modes

Abstract

The human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infection in children and elderly people worldwide. Its genome encodes 11 proteins including SH protein, whose functions are not well known. Studies show that SH protein increases RSV virulence degree and permeability to small compounds, suggesting it is involved in the formation of ion channels. The knowledge of SH structure and function is fundamental for a better understanding of its infection mechanism. The aim of this study was to model, characterize, and analyze the structural behavior of SH protein in the phospholipids bilayer environment. Molecular modeling of SH pentameric structure was performed, followed by traditional molecular dynamics (MD) simulations of the protein immersed in the lipid bilayer. Molecular dynamics with excited normal modes (MDeNM) was applied in the resulting system in order to investigate long time scale pore dynamics. MD simulations support that SH protein is stable in its pentameric form. Simulations also showed the presence of water molecules within the bilayer by density distribution, thus confirming that SH protein is a viroporin. This water transport was also observed in MDeNM studies with histidine residues of five chains (His22 and His51), playing a key role in pore permeability. The combination of traditional MD and MDeNM was a very efficient protocol to investigate functional conformational changes of transmembrane proteins that act as molecular channels. This protocol can support future investigations of drug candidates by acting on SH protein to inhibit viral infection. Graphical Abstract The ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domainᅟ.

A Respiratory Syncytial Virus Vaccine Based on the Small Hydrophobic Protein Ectodomain Presented With a Novel Lipid-Based Formulation Is Highly Immunogenic and Safe in Adults: A First-in-Humans Study

“…In vitro studies showed that SH inhibits apoptosis by blocking a tumor necrosis factor–mediated signaling pathway [ 19 ]. SH could thus promote viral replication by interfering with the host immune response and prolong viral replication in the host cell [ 20 ]. In preclinical studies in mice and cotton rats, SHe-vaccinated and intranasally challenged animals had reduced RSV replication, and SHe-specific antibodies were detected bound to the surface of RSV-infected cells [ 8 ].…”

Variability analysis and inter-genotype comparison of human respiratory syncytial virus small hydrophobic gene

“…In group A strains, H51 (which is missing from RSV5–13) is a crucial residue in the regulation of SH ion channel activity [ 30 ]. Together with H22, H51 plays a key role in the opening and closing mechanism of the SH pentameric pore, since they are located in strategic places within the chains, close to the N- and C-termini [ 30 , 31 ]. An alternative amino acid at position 51 (Y, a non-basic amino acid) has been reported before, in a Brazilian GA5 strain from 2004 [ 28 ], but so far there were no reports of the deletion observed in RSV5–13.…”

A Review of Therapeutics in Clinical Development for Respiratory Syncytial Virus and Influenza in Children

“…One of these is targeting the third surface protein, the SH-protein, which most likely is involved in RSV pathogenicity rather than replication. 33 This novel mechanism is also the focus of vaccine investigations. 32 Other options continue to focus on the nucleocapsid.…”