Objective
Problem:
A high resolution structure alone cannot provide a full understanding of protein structure-function relationships. It is necessary to know also the forces that form the basis of protein functional properties. Among these forces, the fundamental importance of electrostatic interactions is evident from the pH, ionic strength and counterion dependence of protein function. No general and comprehensive approach exists to predict the pK values of titratable groups and hence the ionization behaviour of proteins. Existing theories and computational methods do not account for the conformational heterogeneity of proteins in solution nor for the relationship between electrostatics and the thermodynamics of protein-solvent interactions.
Solution
The main goal of the work proposed in this project is to improve this situation by developing better theoretical and computational methods to describe electrostatic interactions. This goal will be achieved through a combination of experimental and theoretical methods, using well defined model proteins. For this purpose a multi-disciplinary consortium of 7 teams from 5 Member States of the EU has been drawn together. Among them, 4 are academic groups and 3 are industrial enterprises.
Activities
(i) Determination of the solution structures of proteins and their pH dependent conformational equilibria by improved multidimensional heteronuclear NMR spectroscopy.
(ii) Analysis of the effect of electrostatics on the thermodynamics and kinetics of protein folding and catalysis. We will use leucine zippers and ribonuclease T1 as model proteins. Both proteins are ideally suited for a comprehensive analysis of the structural and thermodynamic parameters that form the basis of protein electrostatics. Results will be used to derive a more accurate description of electrostatic interactions, taking into account the conformational heterogeneity of proteins in solution, as well as the contribution of solvent structuring at the protein-water interface.
(iii) The new methodology will be applied to an analysis of
diisopropylfluorophosphatase, the structure of which will be solved during the course of the project, and to an analysis of the pH dependence of xylanase activity.
Major deliverables:
- A novel methodology for the prediction of electrostatic properties of proteins from structural data;
- A generic computer programme ready for distribution and marketing; - Improved multidimensional heteronuclear NMR spectroscopy techniques; - The three-dimensional structure of diisopropylfluorophosphatase in solution,a novel enzyme of high potential for the detoxification of
organophosphates; Design of mutants for an optimal activity and stability; - Identify xylanase variants with up-shifted pH optimum, a property of high importance to the paper and pulp industry.
Major benefits:
Reciprocal exchange of results and ideas between European centres of expertise in computational chemistry, NMR spectroscopy, biochemistry and biophysics. Economic and ecological impact on the industrial application of enzymes.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences physical sciences thermodynamics
- natural sciences computer and information sciences computational science
- natural sciences physical sciences optics spectroscopy absorption spectroscopy
- natural sciences biological sciences biochemistry biomolecules proteins protein folding
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
141 57 Huddinge
Sweden
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.