An all-atom structure-based potential for proteins: bridging minimal models with all-atom empirical forcefields.
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.
Whitford
Paul C
PC
Center for Theoretical Biological Physics and Department of Physics, University of California at San Diego, La Jolla, California 92093, USA.
Noel
Jeffrey K
JK
Gosavi
Shachi
S
Schug
Alexander
A
Sanbonmatsu
Kevin Y
KY
Onuchic
José N
JN
D000081247:CSK Tyrosine-Protein Kinase; D003198:Computer Simulation; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010940:Plant Proteins / Q000737:chemistry* / Q000378:metabolism; D011392:Proline / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013205:Staphylococcal Protein A / Q000737:chemistry / Q000378:metabolism; D013696:Temperature; D013816:Thermodynamics; D019061:src-Family Kinases
D010455:Peptides; D010940:Plant Proteins; D011506:Proteins; D013205:Staphylococcal Protein A; C093336:chymotrypsin inhibitor 2; D011392:Proline; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases