Dimeric Interactions and Complex Formation Using Direct Coevolutionary Couplings


We develop a procedure to characterize the association of protein structures into homodimers using coevolutionary couplings extracted from Direct Coupling Analysis (DCA) in combination with Structure Based Models (SBM). Identification of dimerization contacts using DCA is more challenging than intradomain contacts since direct couplings are mixed with monomeric contacts. Therefore a systematic way to extract dimerization signals has been elusive. We provide evidence that the prediction of homodimeric complexes is possible with high accuracy for all the cases we studied which have rich sequence information. For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95 angstrom and 1.44 angstrom, respectively. This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation. The identification of dimeric complexes can provide interesting molecular insights in the construction of large oligomeric complexes and be useful in the study of aggregation related diseases like Alzheimer's or Parkinson's.

Includes supplementary information
Biophysics, Proteins--Structure, Alzheimer's disease, Parkinson's disease
Work at the Center for Theoretical Biological Physics was sponsored by the NSF (Grants PHY-1427654 and MCB-1214457), by the Cancer Prevention and Research Institute of Texas (CPRIT) and by the Welch Foundation (Grant No. C-1792). R.N.S. also acknowledges financial support provided by The State of São Paulo Research Foundation (FAPESP) with grant 2013/11950-0.
CC BY 4.0 (Attribution), ©2015 The Authors