BSI Lunchtime Seminar - 17 December

Dr Lucas Rudden (EPFL), The BSI Thesis Prize Lecture
17 December, 12-1 pm

Register to attend in-person or online: https://forms.gle/FnhwgASb8W69aJdA6

The impact of dynamics in protein assembly

"Predicting the assembly of multiple proteins into specific complexes is critical to understanding their biological function in an organism, and thus the design of drugs to address their malfunction. Consequently, a significant body of research and development focuses on methods for elucidating protein quaternary structure. In silico techniques are used to propose models that decode experimental data, and independently as a structure prediction tool. These computational methods often consider proteins as rigid structures, yet proteins are inherently flexible molecules, with both local side-chain motion and larger conformational dynamics governing their behaviour. This treatment is particularly problematic for any protein docking engine, where even a simple rearrangement of the side-chain and backbone atoms at the interface of binding partners complicates the successful determination of the correct docked pose. Herein, we present a means of representing protein surface, electrostatics and local dynamics within a single volumetric descriptor, before applying it to a series of physical and biophysical problems to validate it as representative of a protein. We leverage this representation in a protein-protein docking context and demonstrate that its application bypasses the need to compensate for, and predict, specific side-chain packing at the interface of binding partners for both water-soluble and lipid-soluble protein complexes. We find little detriment in the quality of returned predictions with increased flexibility, placing our protein docking approach as highly competitive versus comparative methods, ultimately providing a method to perform transmembrane protein-protein docking, a field where few docking engines exist. Overall, we find that the structure of a protein alone is inadequate in rationalising its function through predictive docking. Therefore, we must also consider the impact of dynamics in protein assembly."