5 Martin Lecture 092811 by fY7R4421

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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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