In brief

Benzene mapping and molecular dynamics simulations reveal a pocket which helps stabilise the COVID-19 spike protein and boost viral transmissibility.


Secret spike pockets revealed

28 Feb 2023

Molecular simulations uncover a new druggable pocket in SARS-CoV-2’s spike protein which could hold the key to blocking COVID-19 infections.

You can know a lot about a person from the contents of their pockets—perhaps car keys and a cell phone, or candies and wet wipes. It turns out that viruses have pockets too. Discovering the mysteries inside these so-called 'cryptic pockets' may provide clues on how to defeat the virus.

“To date, cryptic pockets have typically been discovered serendipitously,” said Peter J. Bond, Senior Principal Investigator at the Multiscale Simulation, Modelling and Design (MSMD) group at A*STAR’s Bioinformatics Institute (BII). "When that happens, they become a major spur for drug development, as they provide novel sites to target on the virus."

Until now, finding cryptic pockets in experimentally-determined viral structures has been tough: it’s difficult to identify them without a pocket-binding ligand, and those ligands are often blocked by large residues, called glycans, that shield the pocket's opening.

Bond teamed up with scientists from the University of Oxford in the UK and Pennsylvania State University in the US to explore out-of-the-box approaches to locate novel cryptic pockets in the spike (S) protein of SARS-CoV-2. Conventional techniques such as X-ray crystallography aren’t ideal given the highly dynamic nature of glycans. Instead, Bond’s team used a molecular dynamics simulation with benzene probes to map the S protein.

A full-length simulated model of the SARS-CoV-2 spike protein’s structure, showing the newly discovered cryptic pocket (inset) uncovered by a benzene probe.

With this method, the scientists discovered a never-before-seen cryptic pocket tucked under the 617-628 loop of the S protein, illuminating a new angle to fight COVID-19 infections. This particular pocket is located in a region thought to play a critical role in dialling up viral transmissibility.

“Our data show that this loop can adopt a bimodal conformation, transitioning between an unstructured loop and a stabilising alpha-helix,” said Bond, adding that drugs that bind to this cryptic pocket could potentially interfere with these loop dynamics, thereby stopping the virus from infecting human cells.

The newly discovered cryptic pocket is a hotspot for mutations which have been identified in the Alpha, Gamma and Omicron variants, which Bond said could be a contributing factor in their extensive global spread.

The study highlights how the benzene mapping approach could transform how we look for new COVID-19 vaccines and medicines. “Identifying cryptic pockets experimentally is labour-intensive,” explained Bond. Benzene probes mirror small molecule drugs structurally, and when combined with molecular dynamics simulations, significantly speed up the hunt for druggable cryptic pockets.

The team is currently leveraging this technology to investigate two promising drug candidates which latch on to the 617-628 loop, forcing it to unfold and destabilise the S protein.

The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute (BII).

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Zuzic, L., Samsudin, F., Shivgan, A.T., Raghuvamsi, P.V., Marzinek, J.K., et al. Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein. Structure 30(8), 1062-1074.e4 (2022). | article

About the Researcher

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Peter J. Bond

Senior Principal Investigator

Bioinformatics Institute (BII)
Peter J. Bond is a Senior Principal Investigator at the Multiscale Simulation, Modelling and Design (MSMD) group at A*STAR’s Bioinformatics Institute. His group develops computational models to resolve the dynamics of biomolecules over multiple time and length scales, focusing particularly on mechanisms of infectious disease, the host immune response to bacterial and viral pathogens and therapeutic intervention strategies.

This article was made for A*STAR Research by Wildtype Media Group