Trp-cage is a 20-residue, fast-folding miniprotein which serve as model system in a variety of experimental and computational studies. Despite its simplicity in sequence, the folding mechanism of Trp-cage seem to be complicated. As evidence accumulate, people believe that a native-like intermediate state exist in such a small system. Previous MD simulations already gave good description to the folded structure of the miniprotein, but the enthalpy and entropy were usually not predicted well. By fitting the backbone and side-chain torsion of each amino acid to the PDB coil library distribution, we developed two residue-specific force fields RSFF1 and RSFF2. With RSFF2, we run REMD simulations of 4 Trp-cage mutants, namely 1L2Y, 2JOF, 2JOF K8A and 2JOF Y3A. The four mutants differ only in the helical segment (residue 1 to 8) of the protein, but the difference of the folding midpoint temperatures can be as large as 50 K (for 2JOF K8A and 2JOF Y3A). In our simulations, all the mutants are well folded, and the results are in good agreement with the experimental data, not only for the temperatures of folding midpoint, but also for entropies and enthalpies. 2D plots of free energy surface using a set of order parameters such as RMSD, radius of gyration and native contact suggest that helix form prior to tertiary contact. The comparison between trajectories also give a picture how the mutations influence the thermal stability of folded structure.

Computational study of folding thermodynamics and mechanism of Trp-cage mutants with RSFF2

249th National Meeting (2015)

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