An all-atom structure-based potential for proteins: bridging minimal models with all-atom empirical forcefields

Proteins. 2009 May 1;75(2):430-41. doi: 10.1002/prot.22253.

Abstract

Protein dynamics take place on many time and length scales. Coarse-grained structure-based (Go) models utilize the funneled energy landscape theory of protein folding to provide an understanding of both long time and long length scale dynamics. All-atom empirical forcefields with explicit solvent can elucidate our understanding of short time dynamics with high energetic and structural resolution. Thus, structure-based models with atomic details included can be used to bridge our understanding between these two approaches. We report on the robustness of folding mechanisms in one such all-atom model. Results for the B domain of Protein A, the SH3 domain of C-Src Kinase, and Chymotrypsin Inhibitor 2 are reported. The interplay between side chain packing and backbone folding is explored. We also compare this model to a C(alpha) structure-based model and an all-atom empirical forcefield. Key findings include: (1) backbone collapse is accompanied by partial side chain packing in a cooperative transition and residual side chain packing occurs gradually with decreasing temperature, (2) folding mechanisms are robust to variations of the energetic parameters, (3) protein folding free-energy barriers can be manipulated through parametric modifications, (4) the global folding mechanisms in a C(alpha) model and the all-atom model agree, although differences can be attributed to energetic heterogeneity in the all-atom model, and (5) proline residues have significant effects on folding mechanisms, independent of isomerization effects. Because this structure-based model has atomic resolution, this work lays the foundation for future studies to probe the contributions of specific energetic factors on protein folding and function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • CSK Tyrosine-Protein Kinase
  • Computer Simulation
  • Models, Molecular
  • Molecular Structure
  • Peptides / chemistry*
  • Peptides / metabolism
  • Plant Proteins / chemistry*
  • Plant Proteins / metabolism
  • Proline / chemistry
  • Proline / metabolism
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / chemistry*
  • Proteins / metabolism
  • Staphylococcal Protein A / chemistry
  • Staphylococcal Protein A / metabolism
  • Temperature
  • Thermodynamics
  • src-Family Kinases

Substances

  • Peptides
  • Plant Proteins
  • Proteins
  • Staphylococcal Protein A
  • chymotrypsin inhibitor 2
  • Proline
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases