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43280-G7
A New Approach to Study the Dynamics of Single Molecule Protein Folding

Jin Wang, State University of New York (Stony Brook)

From the year 2006-2007, we have focused our investigation on several aspects of protein folding: the physical effects of configurational dependent diffusion on fast folding dynamics, and biomolecular binding-folding.

1. The physical effects of configurational dependent diffusion on fast folding dynamics:

We show that diffusion can play an important role in protein folding kinetics. We explicitly calculate the diffusion coefficient of protein folding in a lattice model. We found that diffusion typically is configuration- or reaction coordinate-dependent. The diffusion coefficient is found to be decreasing with respect to the progression

of folding toward the native state, which is caused by the collapse to a compact state constraining the configurational space for exploration. The configuration- or position-dependent diffusion coefficient has a significant contribution to the kinetics in addition to the thermodynamic free-energy barrier. It effectively changes (increases in this case) the kinetic barrier height as well as the position of the corresponding transition state and therefore modifies the folding kinetic rates as well as the kinetic routes. The resulting folding time, by considering both kinetic diffusion and the thermodynamic folding free-energy profile, thus is slower than the estimation from the thermodynamic free-energy barrier with constant diffusion but is consistent with the results from kinetic simulations. The configuration- or coordinate-dependent diffusion is especially important with respect to fast folding, when there is a small or no free-energy barrier and kinetics is controlled by diffusion. Including the configurational dependence will challenge the transition state theory of protein folding. The classical transition state theory will have to be modified to be consistent. The more detailed folding mechanistic studies involving phi value analysis based on the classical transition state theory also will have to be modified quantitatively. The results are published in [1].

2. Exploring the Mechanism of Biomolecular Binding-Folding with Single Molecule Dynamics

Combining a single-molecule study of protein binding with a coarse grained molecular dynamics model including solvent (water molecules) effects, we find that biomolecular recognition is determined by flexibilities in addition to structures. Our single-molecule study shows that binding of CBD (a fragment of Wiskott-Aldrich syndrome protein) to Cdc42 involves bound and loosely bound states, which can be quantitatively explained in our model as a result of binding with large conformational changes. Our model identified certain key residues for binding consistent with mutational experiments. Our study reveals the

role of flexibility and a new scenario of dimeric binding between the monomers: first bind and then fold. The results are published in [2].

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