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Intermolecular interactions: affinity and specificity

Intermolecular interactions: affinity and specificity. Inter-University DEA/DES Bioinformatics 2003-2004 Shoshana J. Wodak, SCMBB-ULB. Intermolecular interactions: Affinity and specificity. Protein 2. Protein 1. protein-ligand. protein-protein. protein-DNA.

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Intermolecular interactions: affinity and specificity

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  1. Intermolecular interactions: affinity and specificity Inter-University DEA/DES Bioinformatics 2003-2004 Shoshana J. Wodak, SCMBB-ULB

  2. Intermolecular interactions: Affinity and specificity Protein 2 Protein 1 protein-ligand protein-protein protein-DNA

  3. Affinity of (macro) molecular association P P + L L AB A B + Kd = [A] [B]/[AB] c0 is the concentration defining the standard state; by convention, c0=1 mol.L-1 DGd = -RT ln Kd/ c0

  4. Affinity of (macro) molecular association Main components of DGd = DGint + DGcc +DGent1 +DGentr2 +DGdehyd 1- DGint interactions in AB (vdW elec) vdW ->0; elec ->unfavourable 2- DGcc conformational changes* 3- DGent1 entropic cost of making 1 molecule from 2 -> unfavorable 4- DGentr2 entropy loss of internal degrees of freedom* 5- DGdehyd dehydration (polar and non-polar groups) non-polar-> favourable; polar -> unfavourable *For simplicity sake, contributions 2 and 4 are not considered.

  5. Affinity of (macro) molecular association Examples of 2 complexes hen lysozyme/Fab from HyHel5 mc Ab Kd ≈10–13 M microbial RNase (barnase) /barstar Kd ≈10–10 M Both interfaces are about 50% non polar and contain 11-13 hydrogen bonds. Barnase-barstar has more charged groups making these bonds than HyHel5-lysozyme. This may be one reason why the first complex is more stable. Its Interface is more hydrophobic

  6. Affinity of (macro) molecular association elec vdW non-polar polar -TDS Results of a rough calculation (Janin, 1995)

  7. Accessible surface and interface in macromolecular complexes Positionsof the center of the solvent probe W define the solvent accessible surface (shaded)of molecules 1 and 2. When they form a complex, W is expelled from the interface and some of the accessible surface is lost. The area buried in the complex, The interface area B is: B= ASA1 + ASA2 - ASA 1/2 ASA = Accessible Surface Area

  8. Interface area in protein crystals and protein-complexes. The sample includes 75 interfaces in protein-protein complexes (Lo Conte et al., 1999) and 1260 pairwise interfaces observed in 152 crystal forms of monomeric proteins (Janin & Rodier, 1995) ; for the second type of interfaces, the scale on the left should be multiplied by 20.

  9. Interface areas in protein-protein complexes The majority of the complexes (70%) have interfaces in the range 1200-2000 Å2 The "standard-size" interface has B = 1600±400 Å2 and typically contains 6 - 13, H-bonds

  10. Atomic packing at macromolecular interfaces Voronoi polyhedra and packing volumes The polygon drawn around atom A is the equivalent in two dimensions of the three-dimensionalVoronoi polyhedon. Atom A is accessible to the solvent and the right-most edge of the polygon is defined by the presence of water molecule W. The position of W must be known in order to draw the polygon.

  11. Atomic packing at protein-protein interfaces Histograms of the V/Vo packing ratio, where V is the sum of the Voronoi volume of all interface atoms in a complex, and Vo is the sum of reference volumes for the same atoms. The reference is a set of atoms buried inside globular proteins. Crystallographic water molecules are taken into account when evaluating Voronoi polyhedra.

  12. Docking procedures Predict the structure of the complex from that of the components. Docking solutions Energy

  13. 106 Number of complexes 0 500 1000 1500 Interface area B (Å2) Specific versus non-specific association Native Binding mode Energy spectrum of a protein-protein complex P P + L L m(E) Lysozyme-antibody Complex (simulation) L P Non- native Binding modes Native L L The native association mode is unique, The number of non-native modes is large E being the energy of interaction between P and L, there are m(E) non-native modes having energies between E+dE, n(E)= m(E) e-E/RT is the energy spectrum of the P+L association.

  14. 106 Number of complexes 0 500 1000 1500 Interface area B (Å2) Specific versus non-specific association At thermodynamic equilibrium, the population of non-native associations is distributed throughout the energy spectrum following Boltzmann’s law: n(E) = m(E) e-E/RT = e-G/RT (with G = E-TS, being the free energy, T the temperature and S the entropy) If the native mode has E=0, S=0, and hence, n(0)=1, the total number of non-native modes, and also the ratio of non-native/native modes is: D is the energy gap, and D’ the maximum value of E. Specificity implies a low value of r Energy spectrum of a protein-protein complex D’ Lysozyme-antibody complex D Native

  15. 106 Number of complexes 0 500 1000 1500 Interface area B (Å2) Specific versus non-specific association Energy spectrum of a protein-protein complex A necessary condition for specificity is that D should be large relative to the thermal energy D>> RT But this is not sufficient: competition comes not from the associations modes with E~D but from the modes with higher energy, because there are so many! Lysozyme-antibody complex D Native

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