Details of Grant 

EPSRC Reference:	EP/C001486/1
Title:	Protein dynamics from discrete path sampling
Principal Investigator:	Wales, Professor D
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department:	Chemistry
Organisation:	University of Cambridge
Scheme:	Standard Research (Pre-FEC)
Starts:	01 June 2005	Ends:	31 May 2008	Value (£):	323,451
EPSRC Research Topic Classifications:	Chemical Biology
EPSRC Industrial Sector Classifications:	Healthcare Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Summary on Grant Application Form
Discovering the pathways by which proteins reach their biologically active native state is one of the most active areas of current scientific endeavour. The ability to analyse and predict these pathways on a computer would provide the opportunity for rational design of mutants with particular characteristics, which would have far-reaching consequences for biological chemistry. Unfortunately, the complexity of realistic models for proteins puts such calculations beyond the realm of standard molecular dynamics and Monte Carlo simulation techniques. Two alternative philosophies have therefore evolved instead. The first employs biased Monte Carlo sampling to determine a free energy profile for folding as a function of one or two order parameters. The second uses denaturing conditions to study protein unfolding via molecular dynamics, but under highly non-equilibrium conditions. Neither of these approaches provides genuine dynamical information about folding. Some results have been obtained for Go-type models, but the potential is extensively modified in such studies.The treatment of rare event dynamics in computer simulations is also a very active field because of the obvious applications to complex systems such as proteins and glasses. The development of two key programs in Dr Wales' group, namely OPTIM and PATHSAMPLE, provides a unique opportunity to calculate dynamical properties such as rate constants and transition state ensembles without the time scale limitations of conventional methods. The capabilities of this theoretical framework have already been demonstrated for mechanisms that cannot be treated by molecular dynamics, even using a dynamical path sampling approach. The construction of discrete pathways between products and reactants, using connected sequences of local minima and transition states, can treat free energy barriers of any size efficiently, and can provide rate constants for complex processes such as protein folding.Most of the theory involved and the programming necessary to treat biomolecules has already been done. Successful applications have now been made to two peptides, namely met-enkephalin and the GB1 hairpin, producing true folding rates and mechanisms for these systems. The student who worked on these projects has now left, and the computers that were used are obsolete and must be retired. New equipment and human resources are needed to continue the project and treat larger systems of interest to the protein engineering community.Once the necessary software has been tuned for use on a distributed memory computer the first objective will be to analyse the folding dynamics for CI2 and the B domain of protein A. In both cases high quality experimental data exists, in the form of both rate constants and phi-values. These systems will therefore serve as benchmarks, before the project turns to larger systems. The ultimate goal is to make predictions for proteins where no phi-value data exists, and to identify key residues and mutations that are expected to accelerate or hinder the folding process. Insight from the folding pathways will also be used to develop new protein structure prediction techniques.
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Organisation Website:	http://www.cam.ac.uk