Packing cavities
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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

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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)

Molecular surface connolly

Molecular Surface (Connolly)

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?

Packing cavities

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)

Packing cavities

  • Laskowski, Luscombe, Swindells, and Thornton (1996)

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

Packing cavities

  • 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)

Packing cavities

Jones and Thornton – Patch Analysis,

PP-interface prediction

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

Packing cavities


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

Packing cavities

  • 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)

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