Objective
Phospholipase A2 is a member of an important class of lipid degrading enzymes. To design relevant mutants of possible industrial significance and inhibitors of pharmaceutical use it is necessary to understand the molecular basis of the function of the enzyme. One interesting aspect of the activity of these enzymes is much higher activity for phospholipids in aggregates such as micelles and monolayers than for single phospholipid molecules in water.
The general objective of this project is to understand how phospholipase A2 binds aggregated phospholipids.
Simulation of phospholipid monolayers and phospholipase A2 on an aggregated substrate has been carried out. The monolayer appears to be highly disordered in contrast the Langmuir-Blodgett films studies in other simulations where the headgroups were confined to a planar surface. This indicates the importance of using explicitly defined solvent for the study of monolayers. The simulation of phospholipase A2 at a monolayer is in progress due to the complexity of the simulation and the inherently flexible nature of the monolayers. The enzyme was positioned with the interfacial recognition site towards the monolayer surface with the aim of studying the monolayer phospholipase interactions. A further aim is to study the movement of the substrate in and out of the active site of phospholipase A2.
A reasonable understanding of how phospholipase A2 binds monomeric substrates has been obtained. This understanding is being exploited in engineering phopholipases A2 with modified specificities. Simple electrostatic calculations have been fairly successful in predicting the change in stability of proteins due to charge engineering. Improved calculations indicate large compensating interaction energies for the mutant that did not behave as expected. The activity of a double mutant N89D/E92K is low and suggests that residue 92 is important in interacting with aggregated substrates either directly or possibly via calcium. An understanding of the dynamic behaviour of monolayers of phospholipids has also developed. The monolayers are intrinsically more flexible than bilayers. Explicit description of the water appears to be essential to describe the behaviour of amphiphile monolayers. Simulation of the monolayer-phospholipase complex is now in progress.
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 chemical sciences inorganic chemistry alkaline earth metals
- natural sciences biological sciences biochemistry biomolecules lipids
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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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 (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
9712 CP GRONINGEN
Netherlands
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