An all‐atom structure‐based potential for proteins: Bridging minimal models with all‐atom empirical forcefields

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Abstract
Protein dynamics take place on many time and length scales. Coarse‐grained structure‐based$ {\bf (G{\overline o})} $ 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 Cαstructure‐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 Cαmodel 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. Proteins 2009.