Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 17, Pages 5413-5418Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1419956112
Keywords
transmembrane beta-barrels; de novo 3D structure prediction; evolutionary couplings; maximum-entropy analysis; hydrogen bonding
Categories
Funding
- National Institutes of Health [R01 GM106303]
- Swedish Research Council [VR-NT 2012-5046, VR-M 2010-3555]
- Foundation for Strategic Research
- Vinnova through the Vinnova-JSP Program
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Transmembrane beta-barrels (TMBs) carry out major functions in substrate transport and protein biogenesis but experimental determination of their 3D structure is challenging. Encouraged by successful de novo 3D structure prediction of globular and alpha-helical membrane proteins from sequence alignments alone, we developed an approach to predict the 3D structure of TMBs. The approach combines the maximum-entropy evolutionary coupling method for predicting residue contacts (EVfold) with a machine-learning approach (boctopus2) for predicting beta-strands in the barrel. In a blinded test for 19 TMB proteins of known structure that have a sufficient number of diverse homologous sequences available, this combined method (EVfold_bb) predicts hydrogen-bonded residue pairs between adjacent beta-strands at an accuracy of similar to 70%. This accuracy is sufficient for the generation of all-atom 3D models. In the transmembrane barrel region, the average 3D structure accuracy [template-modeling (TM) score] of top-ranked models is 0.54 (ranging from 0.36 to 0.85), with a higher (44%) number of residue pairs in correct strand-strand registration than in earlier methods (18%). Although the nonbarrel regions are predicted less accurately overall, the evolutionary couplings identify some highly constrained loop residues and, for FecA protein, the barrel including the structure of a plug domain can be accurately modeled (TM score = 0.68). Lower prediction accuracy tends to be associated with insufficient sequence information and we therefore expect increasing numbers of beta-barrel families to become accessible to accurate 3D structure prediction as the number of available sequences increases.
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