This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding protein flexibility and factors that may affect it is important for predicting of protein function and building a functional model applicable in drug design or bio-nano-engineering. Both ligand binding and rearrangement of surrounding water may alter protein flexibility. Contribution of water to the structural, dynamic, and functional properties of proteins is well known but not well characterized. Some buried water molecules may tighten the protein matrix or make it more flexible. Also protein-ligand interactions must compete with interaction with water. In this project we will perform Molecular Dynamics simulations of proteins with ligands, and calculate free energy differences upon protein mutation or ligand binding in order to quantitatively characterize how stability of non-covalent bonds (hydrogen bonds and hydrophobic contacts) alters protein flexibility. Flexibility of the protein will be assessed via recently proposed graph theoretical approach. We are planning to analyze stability, i.e. rates and dynamics of formation and breakage of hydrogen bonds and hydrophobic contacts in three protein systems that differ by size, flexibility, and a shape of ligand-binding cavities. We will also study how water dynamics and hydrogen-bond formation is altered upon protein mutation or binding o
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