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Role of solvation in the affinity and specificity of ligand-protein interactions

Reference	BB/C500679/1
Principal Investigator / Supervisor	Professor Steve Homans
Co-Investigators / Co-Supervisors
Institution	University of Leeds
Department	Inst of Molecular & Cellular Biology
Funding type	Research
Value (£)	97,277
Status	Completed
Type	Research Grant
Start date	04/01/2005
End date	03/01/2007
Duration	24 months

Abstract

Our knowledge of the molecular basis of ligand-protein interactions is extremely limited. This seriously compromises our ability to utilise the enormous wealth of structural data currently available for structure-based drug design. Moreover, with increasing emphasis on biomolecular interactions following the completion of various genome sequencing projects, there is an urgent need to understand and predict the molecular nature of interactions between biomolecules. It is clear from fundamental thermodynamic considerations that both structural (loosely, enthalpic) and dynamic (entropic) considerations are of equal importance in governing the affinity of an interaction. This applies not only to the interacting biomolecules but also to solvent water. In this proposal we focus on the contribution of solvation in two model ligand-protein interactions. While solvent has long been known to make a major contribution to interaction thermodynamics, the quantitation of this has proven to be notoriously difficult. Here, we utilise a theoretical approach whose novelty lies in comparisons between the interaction thermodynamics of a series of closely related ligands, rather than an ab initio approach on a single ligand-protein complex. This approach enables a straightforward application of free energy perturbation (FEP) techniques to the problem, and importantly enables experimental validation of the theoretically derived parameters to a large degree through differences in related experimentally measured thermodynamic parameters.

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	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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