Evolution of protein interfaces in multimers and fibrils

W. Jeffrey Zabel, Kyle P. Hagner, Benjamin J. Livesey, Joseph A. Marsh, Sima Setayeshgar, Michael Lynch, Paul G. Higgs

Research output: Contribution to journalArticle

Abstract

A majority of cellular proteins function as part of multimeric complexes of two or more subunits. Multimer formation requires interactions between protein surfaces that lead to closed structures, such as dimers and tetramers. If proteins interact in an open-ended way, uncontrolled growth of fibrils can occur, which is likely to be detrimental in most cases. We present a statistical physics model that allows aggregation of proteins as either closed dimers or open fibrils of all lengths. We use pairwise amino-acid contact energies to calculate the energies of interacting protein surfaces. The probabilities of all possible aggregate configurations can be calculated for any given sequence of surface amino acids. We link the statistical physics model to a population genetics model that describes the evolution of the surface residues. When proteins evolve neutrally, without selection for or against multimer formation, we find that a majority of proteins remain as monomers at moderate concentrations, but strong dimer-forming or fibril-forming sequences are also possible. If selection is applied in favor of dimers or in favor of fibrils, then it is easy to select either dimer-forming or fibril-forming sequences. It is also possible to select for oriented fibrils with protein subunits all aligned in the same direction. We measure the propensities of amino acids to occur at interfaces relative to noninteracting surfaces and show that the propensities in our model are strongly correlated with those that have been measured in real protein structures. We also show that there are significant differences between amino acid frequencies at isologous and heterologous interfaces in our model, and we observe that similar effects occur in real protein structures.

Original languageEnglish (US)
Article number225102
JournalJournal of Chemical Physics
Volume150
Issue number22
DOIs
StatePublished - Jun 14 2019

Fingerprint

Dimers
proteins
Proteins
Amino Acids
dimers
amino acids
Membrane Proteins
Physics
Protein Subunits
physics
Agglomeration
Monomers
monomers
energy
configurations
interactions

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Physical and Theoretical Chemistry

Cite this

Zabel, W. J., Hagner, K. P., Livesey, B. J., Marsh, J. A., Setayeshgar, S., Lynch, M., & Higgs, P. G. (2019). Evolution of protein interfaces in multimers and fibrils. Journal of Chemical Physics, 150(22), [225102]. https://doi.org/10.1063/1.5086042

Evolution of protein interfaces in multimers and fibrils. / Zabel, W. Jeffrey; Hagner, Kyle P.; Livesey, Benjamin J.; Marsh, Joseph A.; Setayeshgar, Sima; Lynch, Michael; Higgs, Paul G.

In: Journal of Chemical Physics, Vol. 150, No. 22, 225102, 14.06.2019.

Research output: Contribution to journalArticle

Zabel, WJ, Hagner, KP, Livesey, BJ, Marsh, JA, Setayeshgar, S, Lynch, M & Higgs, PG 2019, 'Evolution of protein interfaces in multimers and fibrils', Journal of Chemical Physics, vol. 150, no. 22, 225102. https://doi.org/10.1063/1.5086042
Zabel WJ, Hagner KP, Livesey BJ, Marsh JA, Setayeshgar S, Lynch M et al. Evolution of protein interfaces in multimers and fibrils. Journal of Chemical Physics. 2019 Jun 14;150(22). 225102. https://doi.org/10.1063/1.5086042
Zabel, W. Jeffrey ; Hagner, Kyle P. ; Livesey, Benjamin J. ; Marsh, Joseph A. ; Setayeshgar, Sima ; Lynch, Michael ; Higgs, Paul G. / Evolution of protein interfaces in multimers and fibrils. In: Journal of Chemical Physics. 2019 ; Vol. 150, No. 22.
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