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Packing, Cavities. atomic radii, contact-distance profiles cavities P-P interactions crystal contacts solvent channels de-stabilizing mutations in core (TS mutants?) entropy effects on surface. Surface Calculations. Lee & Richards - solvent accessible surface

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packing cavities
Packing, Cavities
  • atomic radii, contact-distance profiles
  • cavities
  • P-P interactions
  • crystal contacts
  • solvent channels
  • de-stabilizing mutations in core (TS mutants?)
  • entropy effects on surface
surface calculations
Surface Calculations
  • Lee & Richards - solvent accessible surface
    • expanded atom spheres, reentrant surfaces
  • typical water probe radius: 1.4A
  • computation: grid points vs. tangents (algebraic/analytic)
alpha shape theory
Alpha-shape theory
  • Voronoi methods
  • Liang and Edelsbrunner
  • pockets, pockets, depressions – depends on width of opening
packing density
Packing Density

from Richards (1977)

crambin (blue=vdw,


data on compressibility?

Jie Liang and Ken A. Dill (BiophysJ, 2001).

Are Proteins Well-Packed?

  • 636 proteins; 1.4A probe radius
  • proteins are dense (like solids), yet atoms are arranged like liquids (without voids)
  • P=0.76 for hex-packed spheres
  • P=0.74 for protein interiors
  • distribution of number/size of voids is more variable, like a liquid
  • surface area scales linearly with volume, instead of A a V-2/3
clefts active sites
Clefts/Active Sites
  • Liang Edelsbrunner, Woodward (1998)
de stabilizing mutations in core
De-stabilizing mutations in core
  • cavities, tolerance, re-packing
  • Serrano L., Kellis J., Cann P., Matouschek A. & Fersht A. (1992)
  • In barnase, 15 mutants were constructed in which a hydrophobic interaction was deleted
  • strong correlation between the degree of destabilization (which ranges from 0.60 to 4.71 kcal/mol) and the number of methylene groups deleted
  • average free energy decrease for removal of a completely buried methylene group was found to be 1.5±0.6 kcal/mol. This is additive.
  • double-mutants?
  • temperature-sensitive mutants?
side chain contact profiles
Side-chain contact profiles
  • Sippl – knowledge-based potentials
  • Subramaniam – PDF’s
  • dependence: radial distance, sequence separation
protein protein interactions
Protein-protein interactions
  • flat and hydrophobic?
  • Janin
  • Jones and Thornton (1996), PNAS – data on flatness, H-bonds
  • which is predominant: H-bonds vs. salt-bridges vs. hydrophobic interactions?


complementarity of p p interfaces
Complementarity of P-P interfaces
  • shape complementarity
    • measure “gaps” or voids
    • cavities at interfaces (Hubbard and Argos, 1994)
      • more common than in core
      • suggests complementarity doesn’t have to be perfect
    • surface normals:
      • R Norel, SL Lin, HL Wolfson and R Nussinov
LoConte, Chothia, and Janin (1999), JMB.
    • The average interface has approximately the same non-polar character as the protein surface as a whole, and carries somewhat fewer charged groups.
    • However, some interfaces are significantly more polar and others more non-polar than the average.
    • 1/3 of interface atoms becomes completely buried; packing density is similar to core (like organic solids)
    • in high-res structures, remainder of space is filled in by water molecules (making H-bonds)
    • size for “typical” interfaces: 1600±400Å2
electrostatic complementarity
Electrostatic Complementarity
  • McCoy et al. (1997)
    • defined two correlation coefficients between surfaces (summed over contacts): charge complementarity (ion pairs), and electrostatic potentials
    • depends on assignment of partial charges, solvation...
    • examine effect on DG
    • charge correlations: -0.1..+0.1 (insignificant)
    • electrostatic potential correlations: 0.1..0.7 (significant)
  • steering and diffusion (Kozak et al., 1995)
examples of p p interactions
Examples of P-P interactions
  • b-lactamase/BLIP – one of the tightest
  • antibody-antigens (HYHel5)
  • SH2/SH3 and tyrosine kinases
  • PDZ domains
  • calmodulin
  • proteases, kinases (recognize+catalyze)
beta sheet extension
beta-sheet extension
  • arylamine N-acetyltransferase (nat)
    • acetylates isoniazid in M.smegmatis
    • pdb: 1W6F
    • active in solution as both monomer and dimer
    • lower surface area, but many H-bonds
ppi trivia
PPI Trivia
  • obligate vs. transient complexes - affinity
  • differences between antigen-antibody, protease-inhibitor, and rest of complexes
  • induced conformational changes
  • allostery
  • evolutionary conservation at interfaces (Caffrey et al. 2004),
  • correlated mutations? mutational hot spots, evolutionary trace (Lichtarge)
  • why are homodimers so common? (Lukatsky et al, 2007)

succinyl-CoA synthetase



crystal lattice contacts
Crystal-lattice Contacts
  • Carugo and Argos (1997)
  • small: 45%<100Å2, 8%>500Å2
  • properties like rest of surface, so probably random
  • induced changes (rms)?
protein protein docking
Protein-Protein Docking
  • FTDOCK - Gabb, Jackson, and Sternberg (1997)
    • use Fourier transform to evaluate shape correlation function
    • correlation function includes shape and electrostatic complementarity of surfaces
    • try 6912 rotations, Da=15º

grid nodes within 1.8A of

protein atom are “inside”

  • Multidock (Jackson, Gabb, Sternberg, 1998)
    • what about induced fit? alternative side-chain rotamers? domain rotations?
    • need refinement to do scoring of complexes, increase sensitivity to recognize correct interaction
    • add term for solvation energy (soft-sphere Langevin interactions between solvent grid points and surface side-chains)
    • sample different rotamers
    • Betts & Sternberg (1999) – induced fit at interfaces side-chain and backbone movements
GRAMM (Vakser)
    • low resolution protein docking
    • maybe removing details will help...
    • search 6D space for maximal surface overlap (20º rotations)
    • intermolecular overlap function
    • evaluated on a coarse 7Å grid

PatchDock, FireDock (Nussinov & Wolfson)