Ion channels response in physiological conditions: toward a computational framework for nociception

Vincenzo Carnevale, Temple University

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Giacomo Fiorin, Vincenzo Carnevale, Richard Remsing, Christopher MacDermaid, Daniele Granata, Eleonora Gianti, Marina Kasimova, Santhosh Mogurampally, Vivek Yadav, Saleh Al-Khalifa, Kyle Hall

The extraordinary successes achieved in the last years by bioinformatics, structural biology, and functional studies of proteins have produced an unprecedented amount of data that holds promise to shed light on the workings of these molecular machines. Paradoxically these successes highlighted the fact that sequence, structure and function are linked together in a more subtle and complex way than previously thought. Specifically, protein families with recognizable sequence homology and strictly conserved architecture can show a huge functional heterogeneity, as in the case of voltage-gated-like ion channels (VGLCs). The project's goal is to define a coherent theoretical framework to analyse both ensembles of structures and sequences and apply it to the study of ion channel communications.

The project proposes to use the Blue Waters system to address this problem using a combination of accurate free-energy MD calculations and statistical inference analysis of both trajectories and large multiple sequence alignment. The microscopic determinants of mechanical coupling will be identified with the set of residue-residue interactions that are conserved along evolution and are responsible for a specific, functionally oriented structural dynamics. The study will focus on two specific ion channels families gated by different stimuli: transient receptor potential channels and voltage gated cation channels.

The project will bridge the gap in our understanding of molecular processes and neuronal responses, with the potential of significantly advancing large-scale initiatives like the BRAIN in the US and the HUMAN BRAIN in EU. Additionally, the project provides opportunity to involve graduate and undergraduate students in a research activity lying at the interface between the fields of data analytics and bio-molecular physical chemistry. Given the increased relevance of Big Data approaches to drug discovery and the emergence of precision medicine, the skillset and expertise acquired are expected to match the future needs of industry and academia. Furthermore, student recruitment in the project will take advantage of two initiatives. The first is a Professional Masters in Bioinformatics, where the PI is involved in all organizational aspects, from the steering committee to the design of Structural Bioinformatics classes. The second is the MARC U-STAR program designed to mentor underrepresented groups in research, providing financial assistance to prepare students for competitive graduate programs.