A threonine zipper that mediates protein–protein interactions: Structure and prediction

Curran Oi, John D. Treado, Zachary A. Levine, Christopher S. Lim, Kirsten M. Knecht, Yong Xiong, C S O'Hern, Lynne Regan

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
JournalProtein Science
Early online date10 Sep 2018
DOIs
Publication statusE-pub ahead of print - 10 Sep 2018

Keywords

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

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