Molecular Biophysics & Biochemistry 447b3 / 747b3 Bioinformatics

Pat Fleming - Guest Lecturer

Class #?, 2/9/98

Yale University

Surface Analysis of Macromolecules

• Why study surfaces of macromolecules?
  • Receptor-Ligand, Enzyme-Substrate Complementarity
  • Atomic Packing in Macromolecules

Geometric Analysis of Molecules

• Three assumptions usually made
  
  • Atoms have hard sphere radii
  • Unified Atom Representation
  • Structure is static

• Atomic radii variously defined
  • Some threshold electron density value
  • Some value of van der Waals interaction potential

How are commonly used VDW radii calculated?

• Small molecule crystal contacts
  

• Empirical simulations
  

• Combination of both
  

What are comon VDW radii values?

Types of Defined Surfaces

• van der Waals

• Molecular
  • Contact
  • Re-entrant

• Accessible

Calculation of Atomic Packing in Proteins

• Dependence on atom radii

• Analytical Calculation

• Voronoi Good for buried atoms

• Cavities and Void Space
  • Vacuum
  • Water Filled

Buried Hydrophobic Surface upon Protein Folding

• Protein Stability Dependence

• Much of solvent surface is hydrophobic

Interfacial Buried Surface

• Estimate of of interaction energy

• Empirical Parameterization
  • deltaA(p) and deltaA(np)

Occluded Surface

• Extended Ray Analysis

• Different from Buried Surface

Occluded Surface Model Evaluation

• Occluded Surface Theory

• Normalized OS Comparisons

• Detecting Misfolded Proteins

Occluded Surface Packing Analysis

• Packing Value

• Packing of individual residues

• Limits on protein packing with size

• Packing is Evolutionarily Conserved

Protein/Protein Interaction Analysis in Membranes

• Helix/Helix Dimerization

• OS Changes Upon Mutation

• Compare Surface Interaction vs Energy

Locating Binding Site Surfaces

• APROPOS
  • Alpha Shapes

• Locating FK506 Binding Site

Docking Ligands

• DOCK
  • Sperical Modeling