Publication: Research - peer-review › Journal article – Annual report year: 2002
Lipases are efficient catalysts for lipolytic reactions and require a lipid interface for optimal activity. To study the effect of small charged lipid aggregates on the behavior of these enzymes, we have performed molecular dynamics simulations on five different systems. The simulations carried out in periodic boundary conditions and including explicit water molecules were performed for 2 ns. The lipids were either fatty acid molecules or amines to present negatively or positively charged species. The lipids were partially (i.e. mixture of charged and uncharged lipids) or fully charged. The lipids are randomly placed closely to the active site lid. Our results indicate that in all simulations different lipids do not affect the overall protein structure. However, conformational changes and internal motions in the protein are significantly influenced by the presence of the lipid molecules. In an aqueous environment, protein motions are mainly concentrated in three segments, which are Lys53-Asn63, Ser83-Asn86 and the C-terminus. The former region is structurally conserved in the lipase family and has been proposed to be involved in the activation of lipases. Interestingly, in the presence of the lipid molecules these fluctuations are suppressed, which is partly due to the interaction of the C-terminus with the lipid molecules. This may suggest that the C-terminus (which is not conserved in the lipase family) may have an important role in recognizing and binding to different lipid surfaces. In the presence of lipid aggregates, fluctuations are observed in the loops Va197-Lys106, Arg202-Gly214 and Trp223-Thr252. In particular, the flexibility of the loop Va197-Lys106 may have fundamental implications for the activation of lipases. This region has been suggested as a possible 'entering gate' for substrate molecules to the binding cleft.
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- Lipid patch, Molecular dynamics simulations, Molecular modeling, Protein flexibility, Rhizomucor miehei lipase, Structure–function relationships