Dimeric interactions and complex formation using direct coevolutionary couplings.

Ricardo N Dos Santos,Adriano D Andricopulo,Faruck Morcos,José N Onuchic,Biman Jana

doi:10.1038/srep13652

Abstract

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 1.95Å and 1.44Å, 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.

Highlights

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)
Dimeric interactions have to satisfy both monomeric and dimeric structural requirements and we show that these constrains are reflected as direct amino acid couplings in the collection of sequences of a given protein family
The number of coevolutionary constrains needed to accurately reconstitute complexes is much smaller compared to protein structure prediction, making it a promising application to study intermolecular interactions

Summary

Introduction

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). We show that a relatively simple protocol can be used to extract important coevolving dimeric contacts from the monomeric signals obtained using Direct Coupling Analysis (DCA)[22] and that those couplings can be used to predict complexes with high accuracy This concept might not be applicable to all proteins, here we provide evidence that this approach works for a set of 18 different dimeric complexes from different families which cover different classes, folds, conformations as well as complexes with multidomain architectures with different sizes including medium to large proteins (up to 446 aa). The applicability of this idea to a larger number of molecular systems where dimerization or oligomerization plays an important biological role, but the molecular details have not been elucidated yet, is possible as the number of available sequence information increases over time

Methods

Results

Conclusion