Researchers, from the University of Warwick, have used in silico modelling to identify future therapeutic targets for SARS-CoV-2, including the viral spike protein.
SARS-CoV-2 spike protein
The viral spike protein of SARS-CoV-2 is of particular interest in drug- and vaccine- development, due to its involvement in the recognition and fusion of the virus with its host cell. It is a homotrimer and the ectodomain of each monomer consists of an N-terminal subunit (S1) comprising two domains, SA and SB, followed by an S2 subunit forming a stalk-like structure. The S1 is involved in recognition of the human receptor, angiotensin-converting enzyme 2 (ACE2). S2 then promotes fusion with the host cell membrane, which leads to viral entry. Drugs that target the spike protein therefore have the potential to prevent infection of host cells.
Since the discovery of SARS-CoV-2, a plethora of structures have been determined including the ectodomain of the spike protein, as well as other potential vaccine and drug targets. These structures provide the opportunity for drug design using computational biology to identify candidates and optimise lead compounds. However, crystal structures are only able to provide a static view of proteins, whereas proteins are dynamic – a property that is often crucial in drug development. For example, flexibility can affect the thermodynamic properties of drug binding.
In silico modelling for protein flexibility
Assessment of flexibility is often hampered by the long computational times required for molecular dynamic simulations. The researchers behind this study used a recent protein flexibility in silico modelling approach. This approach combines methods for deconstructing protein structure into a network of rigid and flexible units, with a method that explores the elastic modes of motion of this network and geometric modelling of flexible motion.
In this study, they performed analysis on multiple conformational steps using the crystal structures of 287 SARS-CoV-2 related proteins and potential drug targets, as deposited in the Protein Databank (PDB). The aim of this was to gain a comprehensive overview of rigidity and the possible flexible motion trajectories of each protein. They hypothesised that one method of treatment for the virus could be by interfering with the mobility of SARS-CoV-2 proteins, such as the viral spike protein.
Identification of future therapeutic targets for SARS-CoV-2
Focussing on the spike protein, they used their flexibility model to identify a ‘hinge’ mechanism that allows the spike protein to hook onto a cell. This opens up a tunnel in the virus that is likely a means of delivering the infection into the hooked cell. The scientists suggested that by identifying a suitably sized and shaped molecule, researchers could identify existing drugs that could be effective against the virus. This study was unable to look closely at all 287 proteins in the PBD due to time constraints. However, their data provided a reference to identify interesting motions for a particular protein structure that other researchers can use for further modelling of therapeutic potential. Their model allows faster characterisation than traditional computational molecular dynamic simulations, especially for large protein structures such as the spike protein, which has nearly 3000 residues.
This research has provided an efficient method for large-scale screening of protein mobilities. Additionally, their data identified the SARS-CoV-2 spike protein as a potential drug target by identifying the mechanism of host entry, and has also provided a reference for identification of other motions in the virus that could have therapeutic potential.
Image credit: kjpargeter