Original Publication Date
The Journal of Chemical Physics
DOI of Original Publication
Date of Submission
Closely related to the “protein folding problem” is the issue of protein misfolding and aggregation. Proteinaggregation has been associated with the pathologies of nearly 20 human diseases and presents serious difficulties during the manufacture of pharmaceutical proteins. Computational studies of multiprotein systems have recently emerged as a powerful complement to experimental efforts aimed at understanding the mechanisms of proteinaggregation. We describe the thermodynamics of systems containing two lattice-model 64-mers. A parallel tempering algorithm abates problems associated with glassy systems and the weighted histogram analysis method improves statistical quality. The presence of a second chain has a substantial effect on single-chain conformational preferences. The melting temperature is substantially reduced, and the increase in the population of unfolded states is correlated with an increase in interactions between chains. The transition from two native chains to a non-native aggregate is entropically favorable. Non-native aggregates receive ∼25% of their stabilizing energy from intraprotein contacts not found in the lowest-energy structure. Contact maps show that for non-native dimers, nearly 50% of the most probable interprotein contacts involve pairs of residues that form native contacts, suggesting that a domain-swapping mechanism is involved in self-association.
Cellmer, T., Bratko, D., Prausnitz, J. M., et al. Thermodynamics of folding and association of lattice-model proteins. The Journal of Chemical Physics 122, 174908 (2005). Copyright © 2005 AIP Publishing LLC.
Is Part Of
VCU Chemistry Publications