![]() ![]() Work in the McCammon group is supported in part by NSF, NIH, HHMI, CTBP, NBCR, and the NSF supercomputer centers. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: DB was supported by a postdoc fellowship from the Swiss National Science Foundation. Received: FebruAccepted: MaPublished: April 21, 2011Ĭopyright: © 2011 Bucher et al. PLoS Comput Biol 7(4):Įditor: Ruth Nussinov, National Cancer Institute, United States of America and Tel Aviv University, Israel This has implications for understanding ligand binding mechanisms in MBP and related proteins.Ĭitation: Bucher D, Grant BJ, Markwick PR, McCammon JA (2011) Accessing a Hidden Conformation of the Maltose Binding Protein Using Accelerated Molecular Dynamics. A key finding of the study is that the closed form of the protein – adopted by the ligand-bound form – is not observed in the simulations of the ligand-free protein. The relative stabilities of the two states is predicted and corroborated with existing experimental data. In this study, we use atomistic simulations to characterize the flexibility of the MBP protein, and confirm the existence of a hidden semi-closed state. Mechanistic details of this process remain elusive as atomic structures of relevant intermediate conformations are currently lacking. Because these states may display higher affinity for the ligand than the open state, ligand binding may proceed via a “conformational selection” of the most geometrically and chemically favored conformer. However, recent NMR experiments have suggested that the ligand-free protein is flexible enough to visit partially closed states. The interconversion between the 2 forms has been traditionally viewed as a ligand “induced” process. Crystallographic studies have revealed two stable conformations: a ligand-free open form and a liganded closed form. Maltose-binding protein (MBP) is a bacterial protein involved in nutrient uptake. The study provides a detailed description of the conformational space available to ligand-free MBP, and has implications for understanding ligand recognition and allostery in related proteins. Oscillations between open and partially closed states create variations in the shape and size of the binding site. Continuum electrostatic calculations indicate that the repacking of non-polar residues near the hinge region plays an important role in driving the conformational change. We find that a flexible part of the protein called the balancing interface motif (residues 175–184) is displaced during the transformation. Here we describe accelerated MD simulations that provide a detailed picture of the transition between the open and partially closed states, and confirm the existence of a dynamical equilibrium between these two states in apo MBP. Recent NMR paramagnetic relaxation enhancement (PRE) experiments have shown that the maltose binding protein (MBP) - a prototypical member of the PBP superfamily - exists in a rapidly exchanging (ns to µs regime) mixture comprising an open state (approx 95%), and a minor partially closed state (approx 5%). This conformational change is traditionally viewed as a ligand induced-fit process however, the intrinsic dynamics of the protein may also be crucial for ligand recognition. ![]() Upon binding to their respective ligands, PBPs undergo a large conformational change that effectively closes the binding cleft. All PBPs have characteristic two-domain architecture with a central interdomain ligand-binding cleft. Periplasmic binding proteins (PBPs) are a large family of molecular transporters that play a key role in nutrient uptake and chemotaxis in Gram-negative bacteria. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |