Send to

Choose Destination
Protein Sci. 2018 Nov;27(11):1969-1977. doi: 10.1002/pro.3505.

A threonine zipper that mediates protein-protein interactions: Structure and prediction.

Oi C1,2, Treado JD2,3, Levine ZA1,4, Lim CS1, Knecht KM1, Xiong Y1, O'Hern CS2,3,5,6, Regan L1,2,7,8.

Author information

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, 06520.
Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, Connecticut, 06520.
Department of Mechanical Engineering and Materials Science, Yale University, New Haven, Connecticut, 06520.
Department of Pathology, Yale School of Medicine, New Haven, Connecticut, 06520.
Department of Physics, Yale University, New Haven, Connecticut, 06520.
Department of Applied Physics, Yale University, New Haven, Connecticut, 06520.
Department of Chemistry, Yale University, New Haven, Connecticut, 06520.
Institute of Quantitative Biology, Biochemistry and Biotechnology, Center for Synthetic and Systems Biology, School of Biological Sciences, University of Edinburgh.


We present the structure of an engineered protein-protein interface between two beta barrel proteins, which is mediated by interactions between threonine (Thr) residues. This Thr zipper structure suggests that the protein interface is stabilized by close-packing of the Thr residues, with only one intermonomer hydrogen bond (H-bond) between two of the Thr residues. This Thr-rich interface provides a unique opportunity to study the behavior of Thr in the context of many other Thr residues. In previous work, we have shown that the side chain (χ1 ) dihedral angles of interface and core Thr residues can be predicted with high accuracy using a hard sphere plus stereochemical constraint (HS) model. Here, we demonstrate that in the Thr-rich local environment of the Thr zipper structure, we are able to predict the χ1 dihedral angles of most of the Thr residues. Some, however, are not well predicted by the HS model. We therefore employed explicitly solvated molecular dynamics (MD) simulations to further investigate the side chain conformations of these residues. The MD simulations illustrate the role that transient H-bonding to water, in combination with steric constraints, plays in determining the behavior of these Thr side chains. Broader Audience Statement: Protein-protein interactions are critical to life and the search for ways to disrupt adverse protein-protein interactions involved in disease is an ongoing area of drug discovery. We must better understand protein-protein interfaces, both to be able to disrupt existing ones and to engineer new ones for a variety of biotechnological applications. We have discovered and characterized an artificial Thr-rich protein-protein interface. This novel interface demonstrates a heretofore unknown property of Thr-rich surfaces: mediating protein-protein interactions.


hard sphere plus stereochemical constraint model; molecular dynamics simulations; packing; protein structure; protein-protein interaction; steric interactions; threonine

[Available on 2019-11-01]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center