Structured States of Disordered Proteins from Genomic Sequences

Abstract

SUMMARY Protein flexibility ranges from simple hinge movements to functional disorder. Around half of all human proteins contain apparently disordered regions, with little 3D or functional information, and many of these proteins are associated with disease. Building on the evolutionary couplings approach previously successful in predicting 3D states of ordered proteins and RNA, we developed a method to predict the potential for ordered states for all apparently disordered proteins with sufficiently rich evolutionary information. The approach is highly accurate (79%) for residue interactions as tested in over 60 known disordered regions captured in a bound or specific condition. Assessing the potential for structure of over 1000 apparently-disordered regions of human proteins reveals a continuum of structural order with at least 50% with clear propensity for three- or two-dimensional states. Co-evolutionary constraints reveal hitherto unseen structure of functional importance in apparently disordered proteins.

Structure of the peptidoglycan polymerase RodA resolved by evolutionary coupling analysis

“…For the chosen MSAs, evolutionary couplings (ECs) were determined using a pseudo-likelihood maximization (PLMC) 27–29 . A mixture model approach identified 99% percentile probability of being in contact.…”

“…A mixture model approach identified 99% percentile probability of being in contact. We used a combination of commonly used prediction methods to determine secondary structure predictions (PSIPRED 30 and PolyPhobius 31 ) together with secondary structure propensity computed directly from local ECs 29 resulting in the identification 10 TM helices and 3 smaller helices in ECL4 and 2 beta-strands in ECL2. A total of 220 folded models for T. thermophilus RodA were generated for increasing numbers of EC restraints with using the folding protocol in EVfold 9 which itself uses a distance geometry and simulated annealing protocol in CNS 32,33 .…”

“…We concatenated RodA and PBP2A sequences from each species when they were within 10,000 nucleotides of each other based on European Nucleotide Archive (ENA) data downloaded in February 2017 43 , and evolutionary couplings were computed on the complex alignment as previously described 44 . A mixture model approach was used to identify top-scoring contacts, both within individual monomers and between RodA and PBP2, and to assign a probability to each contact of being within the tail of the distribution of coupling scores as described previously 29 . This scoring method is accurate for predicting whether or not proteins interact as well as which residues are in contact 10 .…”

AlignmentViewer: Sequence Analysis of Large Protein Families

“…MSA is a basic step in many analysis workflows, including: protein (i) structure prediction (Marks et al , 2011), (ii) structure detection in flexible ('disordered') domains (Toth-Petroczy et al , 2016), (iii) function prediction (Tamames et al , 1998) and (iv) intracellular localization (Goldberg et al , 2014).…”

On protein structure, function and modularity from an evolutionary perspective

“…[16,47] In this thesis, and in other works, epistasis has been employed to study function in IDPs. [132,108] Furthermore, since also IDPs seem to contain small functional modular elements, it is a tantalizing idea that they also could be supported by the protein prime model. Evidence exists that IDPs contain functional short molecular recognition features (MoRFs) [136] and transiently structured islets that form fuzzy complexes upon interaction [10,134,66].…”