Core D4: Computational Modeling

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All the efforts within the Membrane Protein Structural Dynamics Consortium (MPSD) are aimed at gaining a deep mechanistic perspective on membrane protein function, linking structure to dynamics. Computation is expected to play a fundamental role in this process, as every Bridging Project (BP) comprises a computational component aiming to (1) analyze results, (2) help interpret structural and dynamical data, and (3) construct models/hypotheses to make predictions that will be tested experimentally in an iterative process that takes advantage of the wide range of interdisciplinary collaborations and resources enabled by this grant. For these reasons, the proposed Computational Modeling Core D4, referred to as CMC, is a central unifying component of the Consortium offering shared perspectives and correlated mechanistic interpretations among the BPs by virtue of ovedapping teams and common validated approaches. Membrane proteins can be considered to function as "molecular machines" that need to change shape and visit many conformational states to perform their function, mostly through complex allosteric mechanisms. To understand how membrane proteins perform such functions, and how this function is regulated and/or modified by disease (e.g., naturally occurring mutations), it is necessary to have detailed knowledge about all those conformational states as well as the reaction pathway connecting them. A profound mechanistic understanding of membrane proteins and their biological function will be recognized by one's ability to make quantitative and accurate predictions of structure, dynamics and function from computational models. Undeniably, sophisticated computations are already an integral part of biomolecular research on membrane proteins [1, 2]. Nonetheless, the collaborative research undertaken with the BPs in this Grant points out that current methodologies would significantly benefit from a more unified approach across multiple scales, and from a close integration of computational and experimental efforts. The computational approaches would also have a greater impact if they became more routinely accessible to all investigators (experimentalists and theoreticians alike). Clearty, additional advances and improvements are needed to address the challenging problems presented by membrane protein systems. A judicious long-term strategy about the role of computation in the investigation of biomolecular systems must ensure that efforts are invested to respond to both the need for dissemination and impact, and the continued development of novel methodologies. This view is incorporated in the overall goal of the CMC to provide and develop state-of-the-art methods and "tools" required for studying the mechanisms of function of complex membrane protein systems.