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Folding Trp-Cage to NMR Resolution Native Structure Using a Coarse-Grained Protein Model

Feng Ding ^*, Sergey V. Buldyrev  and Nikolay V. Dokholyan ^*

^* Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina 27599; and Center for Polymer Studies, Boston University, Boston, Massachusetts 02215

Correspondence: Address reprint requests to Feng Ding, E-mail: fding{at}unc.edu; or Nikolay V. Dokholyan, E-mail: dokh{at}med.unc.edu.

We develop a coarse-grained protein model with a simplified amino acid interaction potential. Using this model, we perform discrete molecular dynamics folding simulations of a small 20-residue protein—Trp-cage—from a fully extended conformation. We demonstrate the ability of the Trp-cage model to consistently reach conformations within 2-Å backbone root-mean-square distance from the corresponding NMR structures. The minimum root-mean-square distance of Trp-cage conformations in simulations can be <1 Å. Our findings suggest that, at least in the case of Trp-cage, a detailed all-atom protein model with a molecular mechanics force field is not necessary to reach the native state of a protein. Our results also suggest that the success of folding Trp-cage in our simulations and in the reported all-atom molecular mechanics simulation studies may be mainly due to the special stabilizing features specific to this miniprotein.

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