アブストラクト
| Date | Apr 25, 2018 |
| Speaker | Adnan Sljoka, Department of Informatics, School of Science and Technology, Kwansei Gakuin University, Japan. |
| Title | Lifting the curtain: probing allostery and other biological secrets with high throughput rigidity analysis |
| Abstract |
Advancements in the field of mathematical rigidity theory have opened up a number of exciting opportunities for computational predictions of protein flexibility and their dynamics. In this talk we will review some of the recent developments in this area of research with a focus on probing the mechanism of elusive allosteric regulation of protein function. Allostery refers to an effect of binding at one site to another, often significantly distant functional site on the protein, allowing for regulation of the protein function. Most dynamic proteins are allosteric and allostery has even been coined the ‘second secret of life’, however the molecular mechanisms that give rise to allostery are currently poorly understood. Our rigidity-transmission allostery (RTA) algorithm, a fast computational method provides a mechanical interpretation of allosteric signaling. RTA is designed to predict if mechanical perturbation of rigidity (mimicking ligand binding) at one site of the protein can transmit and propagate across a protein structure and in turn cause a transmission and change in conformational degrees of freedom at a second distant site, resulting in allosteric transmission. We will demonstrate our approach together with experimental NMR validation on enzymes [1], G protein coupled receptors [2] and other proteins as a powerful tool for probing the difficult allosteric control of protein function. Moreover, we will highlight some recent results where our rigidity-based algorithms provided key new insights of affinity maturation of antibody proteins [3], a process which is fundamental to understanding B-cell immunity.
[1] Kim T., Mehrabi P., Sljoka A. et al Ing C., Bezginov A., Pomes R., Prosser S. and Pai E., The Role of Dimer Asymmetry and Protomer Dynamics in Enzyme Catalysis, Science 355, 262, 2017. [2] Ye L., C. Neale, Sljoka A., Pichugin D., Tsuchimura N., Sunahara R., Prosser S. et al, Bidirectional Regulation of the A2A Adenosine G Protein-Coupled Receptor by Physiological Cations, Nature Communication, 1 9:1372, 2018. [3] Jeliazkov J.R., Sljoka A., Kuroda D., Tsuchimura N., Katoh N., Tsumoto K., Gray J.J., Repertoire Analysis of Antibody CDR-H3 Loops Suggests Affinity Maturation Does Not Typically Result in Rigidification, Frontiers in Immunology, 9, 413, 2018. |