Intrinsic Local Balancing of Hydrophobic and Hydrophilic Residues in Folded Protein Sequences

Persistent Link:
http://hdl.handle.net/10150/596407
Title:
Intrinsic Local Balancing of Hydrophobic and Hydrophilic Residues in Folded Protein Sequences
Author:
Borukhovich, Ian
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Release 04-Jan-2018
Abstract:
Protein sequences may evolve to avoid highly hydrophobic local regions of sequence, in part because such sequences promote nonnative aggregation. Hydrophobic local sequences are avoided in proteins even in buried regions, where native structure requirements tend to favor them. In this dissertation, I describe three explorations of this hydrophobic suppression. In Chapter 2, I examine the occurrence of hydrophobic and polar residues in completely buried β-strand elements, and find evidence for hydrophobic suppression that decreases as a β-strand becomes more exposed. In Chapter 3, I present a generalized study of the tendency of local sequences to deviate from the hydropathy (hydrophobicity) expected based on their solvent exposure. First, I examined the hydropathy of local and nonlocal sequence groups over a large range of solvent exposures, within folded protein domains in the ASTRAL Compendium database; second, I calculated the tendency of residues within 10 positions of a nonpolar or polar reference residue to deviate from the hydropathy expected based on their structural environment. Both analyses suggested that protein sequences exhibit 'local hydropathic balance' across a range of 6-7 residues, meaning that polar and nonpolar residues are more dispersed in the sequence than expected based on solvent exposure patterns. This balance occurs in all major fold classes, domain sizes and protein functions. An unexpected finding was that it partly arises from a tendency of buried or exposed residues to be flanked by polar or nonpolar residues, respectively. This relationship may result from evolutionary selection for folding efficiency, which might be enhanced by reduced local competition for buried or exposed sites during folding. Finally, in Chapter 4, I present several exploratory analyses, including a decision-tree approach, to visualize the influence of a large number of sequence-structure properties on residue hydrophobicity. Overall, the work in this dissertation confirms that hydrophobic suppression and local hydropathic balance in general are intrinsic properties of folded proteins. I speculate that local hydropathic balance results from selection for reduced aggregation propensity, increased folding efficiency and increased native state specificity. The concept of local hydropathic balance might be used to improve the properties of designed and engineered proteins.
Type:
text; Electronic Dissertation
Keywords:
negative selection; polar patterning; Protein folding; protein misfolding; sequence hydrophobicity; Biochemistry; folding landscape
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Biochemistry
Degree Grantor:
University of Arizona
Advisor:
Cordes, Matthew H.J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleIntrinsic Local Balancing of Hydrophobic and Hydrophilic Residues in Folded Protein Sequencesen_US
dc.creatorBorukhovich, Ianen
dc.contributor.authorBorukhovich, Ianen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.releaseRelease 04-Jan-2018en
dc.description.abstractProtein sequences may evolve to avoid highly hydrophobic local regions of sequence, in part because such sequences promote nonnative aggregation. Hydrophobic local sequences are avoided in proteins even in buried regions, where native structure requirements tend to favor them. In this dissertation, I describe three explorations of this hydrophobic suppression. In Chapter 2, I examine the occurrence of hydrophobic and polar residues in completely buried β-strand elements, and find evidence for hydrophobic suppression that decreases as a β-strand becomes more exposed. In Chapter 3, I present a generalized study of the tendency of local sequences to deviate from the hydropathy (hydrophobicity) expected based on their solvent exposure. First, I examined the hydropathy of local and nonlocal sequence groups over a large range of solvent exposures, within folded protein domains in the ASTRAL Compendium database; second, I calculated the tendency of residues within 10 positions of a nonpolar or polar reference residue to deviate from the hydropathy expected based on their structural environment. Both analyses suggested that protein sequences exhibit 'local hydropathic balance' across a range of 6-7 residues, meaning that polar and nonpolar residues are more dispersed in the sequence than expected based on solvent exposure patterns. This balance occurs in all major fold classes, domain sizes and protein functions. An unexpected finding was that it partly arises from a tendency of buried or exposed residues to be flanked by polar or nonpolar residues, respectively. This relationship may result from evolutionary selection for folding efficiency, which might be enhanced by reduced local competition for buried or exposed sites during folding. Finally, in Chapter 4, I present several exploratory analyses, including a decision-tree approach, to visualize the influence of a large number of sequence-structure properties on residue hydrophobicity. Overall, the work in this dissertation confirms that hydrophobic suppression and local hydropathic balance in general are intrinsic properties of folded proteins. I speculate that local hydropathic balance results from selection for reduced aggregation propensity, increased folding efficiency and increased native state specificity. The concept of local hydropathic balance might be used to improve the properties of designed and engineered proteins.en
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectnegative selectionen
dc.subjectpolar patterningen
dc.subjectProtein foldingen
dc.subjectprotein misfoldingen
dc.subjectsequence hydrophobicityen
dc.subjectBiochemistryen
dc.subjectfolding landscapeen
thesis.degree.namePh.D.en
thesis.degree.leveldoctoralen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineBiochemistryen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorCordes, Matthew H.J.en
dc.contributor.committeememberCordes, Matthew H.J.en
dc.contributor.committeememberHausrath, Andrewen
dc.contributor.committeememberMontfort, Williamen
dc.contributor.committeememberVisscher, Koenen
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.