Mean-field lattice-model IDPs

Binding Affinity & Specificity


Travis Hoppe, Robert Best

Biophysical Society Meeting, 2015



National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Laboratory of Chemical Physics (LCP), Theoretical Biophysical Chemistry (TBC)


Slide source at https://github.com/thoppe/Presentation_Research_IDP

Intrinsically disordered proteins

Structure

  • Lack tertiary structure (disorder!)
  • Different primary structure (residue propensity)
  • More charged, less hydrophobic and aromatic residues

Binding

Function

  • Linkers (entropic chains), Chaperones, HIV transcription (TAT)
  • Often found in signaling pathways, centers of protein hubs
  • Binding specificity, with lower affinity


Questions

  • What advantages do IDPs have over traditional proteins?
  • How to incorporate the crowded cellular environment?


Modeling

IDPs: Folding Sampling


Goal: Develop a model for IDP binding interactions.

Statistical Potentials

Residue-residue interactions, quasi-chemical lattice-gas




Potentials constructed from Top 8000 Protein Database, Richardson Group

Statistical potentials have predictive power





[1] Coarse-grained models for simulations of multiprotein complexes, Kim & Hummer, J Mol Biol(375):1416-33
[2] Properties of Integral Membrane Protein Structures, Ulmschneider, Sansom & Nola, Proteins(59):252-265
[3] Pairing preferences at protein-protein interfaces, Glaser, et al., Proteins:43(2) 89-102

Residue-residue interaction matrix, MJ


Other statistical potentials: Tanaka and Scheraga (1976), Spil (1990), Miyazawa and Jernigan (1996),
Betancourt and Thirumalai (1999), Skolnick, Kolinski and Ortiz (2000)

MJ Contact energy, from structure




Mean-field (MF) energy, from sequence

MF Energy distributions: Physically reasonable



IDP Propensity, Coeytaux & Poupon, Bioinformatics (2005)
Hydrophilicity index, Kyte & Doolittle, J. Mol. Biol. (1982)
Amyloidogenic regions, Garbuzynskiy et. al. Bioinformatics (2010)

Protein Networks

  • Target protein interacts with a range of possible surfaces.
  • Measure average binding affinity of protein to surfaces.
  • Measure binding specificity of protein to surfaces.
  • A priori structure is unknown; simplest model first.

Protein-complex energy


Pairwise decomposition of protein complex energy; Binding affinity


Contact matrix is not symmetric


Specificity score: Define "decoys" as weakly bound
structures in protein network.

Binding affinity

Binding specificity

Summary & Future Work

  • MF IDP's bound to native structures show increased
    specificity with lower affinity.




What's next? Add structure to mean field calculations.
Lattices may be optimal for IDP's, they can reproduce native-energies but quickly sample extended conformational space.

Thank you.

Questions?


Laboratory of Chemical Physics