Understanding Essential Protein Dynamics through the Anharmonic Properties of Thermally Excited Vibrations

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The selectivity of orthosteric drugs is often limited by the structural similarity of their binding sites in homologous proteins, while allosteric binding sites are far less conserved. This allows allosteric drugs to bind a target protein with higher selectivity, which reduces the potential for side-effects and lowers drug toxicity. However, allosteric drug discoveries have been limited to serendipitous observations because rational allosteric drug design strategies face several inherent challenges. These challenges are directly related to current limits in the predictability of protein conformational fluctuations and collective dynamics that are central to the mechanisms of allosteric drugs. The objective of this project is the development of computational methods to facilitate the rational design of allosteric drugs via predictions of protein conformational fluctuations and collective dynamics from all-atom simulations. In principle, all-atom molecular dynamics simulations can directly explore protein conformational dynamics but require sampling on timescales of milliseconds to seconds for systems of pharmacological interest. Even with state-of-the-art enhanced sampling techniques, the associated computational costs and hardware requirements (special purpose computers, national supercomputers, large distributed computing networks) limit such applications to a small number of systems. This project aims to make the computational discovery of allosteric mechanisms in proteins more efficient and achievable with computer hardware available in most research laboratories and universities. To this end, the methods developed for this project maximize the information on inherent protein dynamics that can be extracted from molecular dynamics simulations. These methods will initially be applied to identify allosteric mechanisms in matrix metallo-proteinases (MMPs), which represent a family of structurally homologous proteins involved in the degradation of the extracellular matrix. Several members of the MMP family have been identified as drug targets in the context of chronic inflammatory disease and cancer metastasis. MMPs feature a highly conserved catalytic center, which results in a low selectivity of orthosteric small molecule inhibitors for individual MMPs and limits their therapeutic use. This project aims to identify allosteric mechanisms in MMPs that enable the targeted development of highly selective allosteric MMP inhibitors as potential drug candidates. The methods developed for this project are general and not specific to MMPs. They will thus be applicable for the identification of allosteric mechanisms in other drug target proteins and will be made available as open- source software.