Structural causes, control mechanisms and consequences of small-molecule protein binding promiscuity

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The cellular environment is a crowded, unforgiving environment far from the controlled conditions encountered in test tubes. From a thermodynamic point of view, in these conditions, there should be competition between proteins for small-molecules and vice versa. The extent to which this occurs is influenced by the evolution of protein function, that requires not only the ability to bind specific small molecules but also the mechanisms to keep in check the competition. This phenomenon of small-molecule/protein binding promiscuity has been largely ignored over the years and it is crucial in improving our knowledge of molecular recognition, evolution and cellular function. The proposed research program will develop the tools and resources necessary to study the structural causes and control mechanisms of small-molecule protein binding promiscuity at a systems level. The primary objectives of the proposed research program are: 1. The development of methods for the detection of binding site similarities 2: The development of methods for the simulation of dynamic aspects of protein function, and 3. The mapping of experimental and modelled protein structural information into reconstructed metabolic networks to integrate structural and systems biology and use of the methods developed to understand molecular recognition and exploit it in drug design. The novelty of the research plan lies in the powerful new methods proposed and their use to understanding molecular recognition from a structural systems biology point of view. The proposed research plan will develop and integrate structural computational biology tools as well as bio- and chemo-informatics resources and represents a new paradigm for understanding molecular recognition. The interdisciplinary nature of this program will contribute to the formation of students from diverse backgrounds to work at the interface of chemistry, molecular biology, physics and computer sciences.