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(A) Molecular dynamics simulations of native proteins and folding intermediates and correlation with NMR protection factors

Reference	JE412678
Principal Investigator / Supervisor	Dr Richard Sessions
Co-Investigators / Co-Supervisors	Professor Anthony Clarke, Dr Christopher Dempsey
Institution	University of Bristol
Department	Biochemistry
Funding type	Research
Value (£)	68,496
Status	Completed
Type	Research Grant
Start date	10/05/2000
End date	10/11/2000
Duration	6 months

Abstract

The applicants have previously shown a semi-quantitative relationship between NMR amide-exchange protection factors of 25-35 residue peptides and the corresponding persistence of hydrogen bonding interactions during molecular dynamics simulations. It is our intention to systematically investigate whether such relationships can also be observed in protein-sized systems. To develop this approach, we propose initially applying the methods to CD2.d1 a 98 residue fragment corresponding to domain 1 of the cell adhesion protein, CD2. This molecule has been intensively studied at Bristol, and a wealth of structural (crystallographic), dynamic (NMR exchange) and folding (kinetic, thermodynamic) data have been amassed on both the wild type and several mutant proteins. Thermal unfolding during the dynamics simulations will be used to investigate partially structured states of the protein. Analysis of the data from these simulations should reveal the underlying structural reason for the observed behaviour of these molecules. This work can only be carried out on the kind of computer system bid for here, which will allow us to generate 1ns trajectories per 2 weeks, at a conservative estimate. In the longer term, it is anticipated that this methodology will be applied to other systems, such as the human prion protein, after this initial proof-of-concept.

Summary

unavailable

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Joint Equipment Initiative 1999 (JE4) [1999]
Funding Scheme	X – not Funded via a specific Funding Scheme

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