Seminar: Allostery and entropy in molecular recognition

I will address two topics:1. Allosteric networks and iron pathways in eukaryotic and prokaryotic ferritins – Ferritin-like molecules show a remarkable combination of the evolutionary conserved activity of iron uptake and release that engage different pores in the conserved ferritin shell. It was hypothesized that pore selection and iron traffic depend on dynamic allostery with no conformational changes in the backbone. In order to detect a long-range network of cooperative residues, we have developed a network-weaving algorithm (NWA) that passes threads of an allosteric network through highly correlated residues using hierarchical clustering. The NWA was applied to four representative 24-meric ferritins (P.ae BfrB, P.ae FtnA, bullfrog M and L Ftns) in conjunction with a packing-on elastic network model. We have detected the allosteric networks in all four ferritins and characterized their relationship to the iron pathways. The results show that the allosteric networks engage species-specific pores and a ferroxidase center in agreement with experimental observations of iron transport. The residue-residue correlations and the resultant structure of the allosteric networks depend significantly on the ferritin shell packing, which, in turn, depends on protein sequence composition. This relationship explains the diversity of iron pathways suggested by experimental approaches.2.  Accounting for binding entropy in protein-ligand docking – I will introduce several statistical-thermodynamic methods for calculating protein-ligand binding entropy in the context of predicting structures of protein-ligand complexes. These methods have shown substantial improvement in docking accuracy for AutoDock, D/F/G/X-Score, LigScore, PLP, LUDI, ChemScore, PMF, and DrugScore scoring functions. I will also discuss a relationship between binding entropy and a ligand propensity to bind in wide energy wells.

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