title: Overcoming residual frustration in domain-swapping: the roles of disulfide bonds in dimerization and aggregation.
abstract: The prevalence of domain-swapping in nature is a manifestation of the principle of minimal frustration in that the interactions designed by evolution to stabilize the protein are also involved in this mode of binding. We previously demonstrated that the Symmetrized-Go potential accurately predicts the experimentally observed domain-swapped structure of Eps8 based solely on the structure of the monomer. There can be, however, multiple modes of domain-swapping, reflecting a higher level of frustration, which is a consequence of symmetry. The human prion and cyanovirin-N are too frustrated to form unique domain-swapped structures on the basis of the Symmetrized-Go potential. However, supplementing the completely symmetric model with intermolecular and intramolecular disulfide bonds in the prion and cyanovirin-N proteins, respectively, yielded unique domain-swapped structures with a remarkable similarity to the experimentally observed ones. These results suggest that the disulfide bonds may sometimes be critical in overcoming the intrinsic frustration of the symmetrized energy landscapes for domain-swapping. We also discuss the implications of intermolecular disulfide bonds in the formation of mammalian prion aggregates.
authors.affiliation: Center for Theoretical Biological Physics, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Cho
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Levy
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wolynes
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D001703:Biophysics / Q000379:methods*; D002352:Carrier Proteins / Q000737:chemistry; D019295:Computational Biology / Q000295:instrumentation* / Q000379:methods; D019281:Dimerization; D004220:Disulfides; D006801:Humans; D015233:Models, Statistical; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011328:Prions / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013696:Temperature
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D004220:Disulfides; D011328:Prions; C107733:cyanovirin N