Protein knots & protein-ligand binding pathways

A little bit more progress in our molecular VR research work… Building on the framework which we demoed in Salt Lake City at Supercomputing 2016, we’ve started looking at applications to biomolecular systems with interesting conformational dynamics which are difficult to observe using standard molecular simulation workflows. The two videos that I’ve posted here were made by PhD students Mike O’Connor and Helen Deeks. The videos show Mike & Helen’s view within the real-time Nano Simbox virtual reality environment as they utilize a wireless set of “atomic tweezers” to steer a real-time molecular dynamics simulation (i.e., a real-time GPU accelerated implementation of the AMBER force field).

The first video shows the steps which Helen took to tie a knot in a 10-alanine peptide. Knotting is an interesting application for the VR Simbox, because the manipulations required to tie a knot in a molecular structure are actually pretty complex. For example, if I was going to write some code to tie a molecular knot, it would end up being a rather complicated little piece of software. However, tying knots is the sort of thing that’s actually rather straightforward and intuitive for a human, because we all tie knots all the time (and the sailors and knitters amongst us are even more expert)… There’s a lot of fundamental interest in understanding the kinetic mechanism of knotting, given that 1 – 2% of all known proteins are knotted…

The second video shows the steps which Mike took to interactively dock a single benzylpenicillin drug molecule (initially floating in free solvent) into the active sight of the β-lactamase enzyme. β-Lactamases are amongst the most common molecular tool used by bacteria to break down important classes of β-lactam antibiotics like benzylpenicillin, causing them to lose their antibiotic effect. Understanding the mechanism of β-Lactamases is therefore essential to make progress addressing the growing problem of anti-microbial resistance.

In both of these videos, Mike & Helen were able to generate dynamics pathways which would simply never be observed using conventional simulation methodologies. We’re now working on methods for analysing the user-generated pathways – i.e., enabling us to map conformational states, and also to calculate free energies. The idea is that this will provide insight into conformational kinetics and mechanisms. Stay tuned!

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