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Electrostatics in intrinsically disordered proteins

University of British Columbia

Protein-protein interactions are fundamental to many biological processes. A large proportion of proteins have been identified as partially or entirely disordered in their native state. Disordered protein regions appear to be especially adept for facilitating interactions and are often important for signaling and regulation. This is a relatively young field compared to the extensively studied structured proteins, which means the data available is not as abundant and well characterized. Consequently, the first goal of this thesis is to use a structure-based method to identify intrinsically disordered protein (IDP) complexes. We hypothesize that we can take advantage of the tendency of intrinsically disordered segments to adopt extended structures when bound to globular proteins to separate them from natively structured proteins. Radius of gyration is used to measure the extendedness of protein chains in protein data bank structures. The dataset of selected extended protein chains is then verified to be enriched in disorder through sequence based prediction. The second goal of the thesis is to characterize the identified IDP complexes. This involved an attempt to analyze the compaction of intrinsically disordered segments upon binding and analysis of the interface residue composition. Analysis of the interface residue composition revealed an interesting disparity between the residue compositions across the IDP complex interface. An enrichment of hydrophobic and depletion of charged residues on the IDP side of the interface seems to suggest that IDP interactions are relatively unspecific due to strong hydrophobic contributions. Their importance in signaling and regulation as well as studies that suggested highly specific interactions led us to investigate the polar interactions of IDP complexes. Computational alanine scanning and continuum electrostatic calculations on IDP complexes reveal a class of protein-protein interaction that has high electrostatic complementarity in comparison to structured protein complexes. Charged residues on the IDP interface make greater contribution to binding compared to those of structured proteins. Furthermore, large desolvation penalties and Coulombic interactions balance out to contribute to highly specific yet low affinity interactions.

Text

2013-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/43451

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/