TY - GEN A1 - Held, Martin A1 - Metzner, Philipp A1 - Prinz, Jan-Hendrik A1 - Noe, Frank T1 - Mechanisms of protein-ligand association and its modulation by protein mutations N2 - Protein-ligand interactions are essential for nearly all biological processes, and yet the bio- physical mechanism that enables potential binding partners to associate before specific binding occurs remains poorly understood. Fundamental questions include which factors influence the formation of protein-ligand encounter complexes, and whether designated association path- ways exist. In this article we introduce a computational approach to systematically analyze the complete ensemble of association pathways and to thus investigate these questions. This approach is employed here to study the binding of a phosphate ion to the Escherichia coli Phosphate Binding Protein. Various mutants of the protein are considered and their effects on binding free energy profiles, association rates and association pathway distributions are quantified. The results reveal the existence of two anion attractors, i.e. regions that initially attract negatively charged particles and allow them to be efficiently screened for phosphate which is specifically bound subsequently. Point mutations that affect the charge on these attractors modulate their attraction strength and speed up association to a factor of 10 of the diffusion limit and thus change the association pathways of the phosphate ligand. It is demonstrated that a phosphate that pre-binds to such an attractor neutralizes its attraction effect to the environment, making the simultaneous association of a second phosphate ion unlikely. Our study suggests ways how structural properties can be used to tune molecular association kinetics so as to optimize the efficiency of binding, and highlights the importance of kinetic properties. KW - protein-ligand binding KW - association pathways KW - Phosphate Binding Protein KW - Brownian dynamics KW - Transition Path Theory Y1 - 2012 UR - https://opus4.kobv.de/opus4-matheon/frontdoor/index/index/docId/1097 UR - https://nbn-resolving.org/urn:nbn:de:0296-matheon-10975 ER -