Abstract
The 20 residue Trp-cage mini-protein is one of smallest proteins that adopt a stable folded structure containing also well-defined secondary structure elements. The hydrophobic core is arranged around a single central Trp residue. Despite several experimental and simulation studies the detailed folding mechanism of the Trp-cage protein is still not completely understood. Starting from fully extended as well as from partially folded Trp-cage structures a series of molecular dynamics simulations in explicit solvent and using four different force fields was performed. All simulations resulted in rapid collapse of the protein to on average relatively compact states. The simulations indicate a significant dependence of the speed of folding to near-native states on the side chain rotamer state of the central Trp residue. Whereas the majority of intermediate start structures with the central Trp side chain in a near-native rotameric state folded successfully within less than 100 ns only a fraction of start structures reached near-native folded states with an initially non-native Trp side chain rotamer state. Weak restraining of the Trp side chain dihedral angles to the state in the folded protein resulted in significant acceleration of the folding both starting from fully extended or intermediate conformations. The results indicate that the side chain conformation of the central Trp residue can create a significant barrier for controlling transitions to a near native folded structure. Similar mechanisms might be of importance for the folding of other protein structures.
Highlights
Understanding the molecular details of the structure formation process of biomolecules is still a challenge in molecular biophysics and in structural biology
A two stage folding mechanism was initially suggested by Qui et al [2] based on laser temperature jump spectroscopy and further supported by a thermodynamic study by Streicher et al [4] using differential scanning calorimetry (DSC)
Much has been debated about the folding pathway of the Trp-cage mini protein, it is widely accepted with increasing experimental evidence, that the folding of Trp-cage is not a simple two stage folding mechanism but rather involves semi-stable intermediates along the folding pathway [5,6,7,8,9,14,15]
Summary
Understanding the molecular details of the structure formation process of biomolecules is still a challenge in molecular biophysics and in structural biology. The Trp-cage protein is one of the smallest model proteins of just 20 amino acid residues that adopt a well defined fold with secondary structure elements and a hydrophobic core formed around a central Trp residue [1]. It can fold spontaneously into a stable 3D structure within ,4 ms [2]. Structures of this protein were determined by NMR spectroscopy [1] and recently by X-ray crystallography [3]. A two stage folding mechanism was initially suggested by Qui et al [2] based on laser temperature jump spectroscopy and further supported by a thermodynamic study by Streicher et al [4] using differential scanning calorimetry (DSC)
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