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Learning about Protein-Ligand Interactions Professor Stephen Martin Chemistry and Biochemistry Department The University of Texas at Austin 28 September 2011 Freshman Research Initiative Molecular Recognition in Biological Systems Ka + Ligand Protein Complex Changing structure of ligand leads to changes in binding affinity K’a + Ligand Protein Complex Key Question: How do changes in ligand preorganization, hydrophobicity, hydrogen bonding capability, -cation stabilizing ability, etc. affect energetics in protein-ligand interactions? Why Important: Optimizing protein binding affiniity is critical first step in drug discovery General Features of Protein-Ligand Interactions Hydrophobic H2O H2O H2O Hydrogen Contacts H2O H2O H2O H2O H2O H2O Bonding H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O C–H H2O H–C H2O C–H H O H2O H2O C–H H–C H2O 2 H–C C–H H–C H2O H2O H2O C=O H2O H2O H–N H2O H2O H2O C=O H–N H2O H2O H2O N–H H2O + H2O O=C H2O H2O N–H H2O O=C H2O + H2O H2O H2O H2O H2O H2O –CO2– H2O +H N H2O H2O H2O H2O 3 H2O Kassoc H2O –CO2 – +H 3N H2O H2O H2O H2O H2O –NH3+ H2O –O C H2O H2O 2 H2O H2O H O –NH3+ –O2C H2O H2O H2O H O 2 H2O H2O H2O 2 H2O H2O H2O H2O H2O H2O Salt Bridges H2O H2O H2O H2O H2O H2O H2O Solvated Protein Solvated Ligand Solvated Protein-Ligand Bulk Water Complex Changes in rotational and translational degrees of freedom Shape complementarity of binding surfaces, but conformational changes occur Hydrating water molecules around protein and ligand reorganize and some are released to bulk water – desolvation Formation of non-bonded interactions Gas constant Temperature [P–L] ∆G = ∆H – T∆S = –RTlnKassoc Kassoc = [P][L] Free energy Enthalpy Entropy Non-bonded interactions Order and dynamics Thermodynamics 101 – Applied to Protein-Ligand Interactions Increasing Ligand Affinity by Preorganizing Ligands affinity (Ka) + ∆G Flexible Ligand Protein Ligand-Protein Complex ∆G = ∆H – T∆S = –RTlnKa affinity (K'a) + ∆G' Constrained Ligand more favorable Protein Ligand-Protein Complex ∆G' = ∆H' – T∆S' = –RTlnK'a ∆G' should be more negative than ∆G because ∆S' less negative (more positive) than ∆S by an estimated 2–6 eu (ca 0.6–1.5 kcal/mol at 25 °C) per fully restricted rotor There are various benefits of preorganization in protein-ligand interactions, but no compelling experimental evidence supporting the putative entropic advantage when we started!
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