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dc.contributor.author Cardle, L.
dc.contributor.author Quinn, S.
dc.contributor.author Pritchard, Leighton
dc.contributor.author Dufton, M.
dc.date.accessioned 2010-02-26T14:27:16Z
dc.date.available 2010-02-26T14:27:16Z
dc.date.issued 2003
dc.identifier.citation Cardle , L , Quinn , S , Pritchard , L & Dufton , M 2003 , ' Simple intrasequence difference (SID) analysis: an original method to highlight and rank sub-structural interfaces in protein folds. Application to the folds of ovine pancreatic trypsin inhibitor, phospholipase A(2), chymotrypsin and carboxypeptidase A. ' Protein Engineering, Design and Selection , vol 16 , no. 2 , pp. 87-101 . , 10.1093/proeng/gzg012 en
dc.identifier.issn 1741-0126
dc.identifier.other PURE: 136613
dc.identifier.other dspace: 2160/4123
dc.identifier.uri http://hdl.handle.net/2160/4123
dc.description Pritchard, L., Cardle, L., Quinn, S., Dufton, M. (2003). Simple intrasequence difference (SID) analysis: an original method to highlight and rank sub-structural interfaces in protein folds. Application to the folds of ovine pancreatic trypsin inhibitor, phospholipase A(2), chymotrypsin and carboxypeptidase A.   Protein Engineering, Oxford University Press, 16, (2), 87-101 en
dc.description.abstract We present Simple Intrasequence Difference (SID) analysis, a novel bioinformatic technique designed to help comprehend the properties of protein fold topologies. The analysis grades numerically every residue position in a given protein 3D structure according to the topological situation of the position in the folded chain. This results in an expression of the potential contribution of each residue position and its vicinity towards the integrity of the molecular conformation. Contiguous highly graded residues delineate the sub-structural interfaces that arise from the presence within the molecular fold of discrete domains and sub-domains. This comprehensive rendering of the internal arrangement of chain interfacing helps predict the potential for site-specific inductions (e.g. via mutations or ligand binding) of conformational change in the fold. Whereas SID analysis of single folds can convey an idea of the basic potential for topological adjustment in the protein family, comparative SID analysis of related folds focuses attention on those areas of the family fold where evolutionary changes, activation events and ligand binding have had the most topological impact. For demonstration, SID analysis is applied to the folds of pancreatic trypsin inhibitor (Kunitz), phospholipase A2, chymotrypsin and carboxypeptidase A. We find that many of the potentially vulnerable sub-structural interfaces tend to be protected in the fold interior, in many cases stabilised by disulfide bridges spanning the interface. However, the most prominent interfaces tend to be externally accessible, without remedial stabilisation by disulfide bridges. These latter interfaces are associated so closely with the known functional sites that alterations to the interfacial juxtapositions should influence recognition and catalytic behaviour directly. This shows how side chain mutations, chemical modifications and binding events remote from the sites can nevertheless adjust, via interfacial realignment, the conformations and emergent properties of the sites. The close association also provides clear opportunities for interfacial rearrangements to follow intermolecular recognition events in the sites, facilitating translation of the binding into adjustment of the molecular conformation in areas distant from the sites. As a direct consequence of the topological arrangements, a large proportion of the molecular structure has the capacity to shape the character of the functional sites and, conversely, binding at these sites has the potential to radiate influence to the rest of the molecule. For the enzymes considered, the evidence is consistent with the possibility that primary and secondary binding by the substrate enhances catalytic efficiency by imposing conformational change upon the catalytic centre via adjustments to the fold. This influence may be expressed as favourable adjustment of the catalytic geometry, transition state ensemble, energy propagation pathway, or as a physical strain exerted on the substrate bond to be cleaved. The scale of the adjustments, and their importance to the mechanisms, may have been seriously underestimated. en
dc.format.extent 15 en
dc.language.iso eng
dc.relation.ispartof Protein Engineering, Design and Selection en
dc.title Simple intrasequence difference (SID) analysis: an original method to highlight and rank sub-structural interfaces in protein folds. Application to the folds of ovine pancreatic trypsin inhibitor, phospholipase A(2), chymotrypsin and carboxypeptidase A. en
dc.type Text en
dc.type.publicationtype Article (Journal) en
dc.identifier.doi http://dx.doi.org/10.1093/proeng/gzg012
dc.contributor.institution Aberystwyth University en
dc.contributor.institution Institute of Biological, Environmental and Rural Sciences en
dc.description.status Peer reviewed en


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