(492e) Coarse Reconstruction Of An Effective Folding Free Energy Surface For Src-SH3 Domain Protein

Complex physical systems frequently undergo conformational
transitions between free energy minima separated by a large barrier. The large resultant
disparity in timescales for inter-well and intra-well dynamics greatly limits
the use of conventional all-atom Molecular Dynamics (MD) simulation to study
conformational transitions. To circumvent this difficulty we propose a
synergistic combination of coarse molecular dynamics (CMD) and reverse
integration to extract, on-the-fly, information (in reaction coordinate space)
about the slow dynamics of the system from multiple short microscopic
simulations. In this approach, reaction coordinates are extrapolated
"backward-in-time" using information from their forward time
evolution obtained from the fast relaxation dynamics of the system.

We utilize our method to
reconstruct the two-dimensional folding free energy surface of a simplified
model of src-SH3 domain, a 57 residue protein. The protein is modeled using an
off-lattice C_a
representation associated with a realistic, minimally frustrated Hamiltonian. Previous
experimental and simulation studies of this system indicate that a two-state
folding mechanism is operative with a single free energy barrier separating the
folded and unfolded state. Additionally, the folding process may be effectively
characterized by two empirical, structure-based, reaction coordinates: the
number of native contacts formed, Q, and the number of non-native contacts
formed, A. Here, we use Q and A to map the underlying effective folding free
energy surface of SH3.

The location of the top of the
folding free energy barrier on the (Q, A) surface determined using our approach
is in remarkable agreement with the transition state on the free energy surface
obtained from processing simulation data  from  traditional long-time MD. Furthermore,
the proposed method identifies the folding transition state region with a
significant reduction in the simulation time relative to standard MD.