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Research GBB Molecular Dynamics Group Research

Protein folding initiation sites / Peptide conformations and protein folding

Anton Feenstra investigated the use of a hierarcal classification of the internal motions within a series of proteins to estimate the relative stability of peptide fragments and specific structural motifs.  The aim is to identify fragments that may play a role in the initiation of protein folding or that may fold as single units and used to simplify the description of the folding process. Analysis of internal motions is used to draw a distinction between rigid segments and more flexible connecting regions. Proteins are viewed as having a hierarchy of motions ranging from very short time-scales (ps), at the atomic level, to very long time-scales (minutes), at the level of conformational changes in supra-molecular assemblies. Stable fragments are identified based on the assignment of rigid-like domains in an extensive series of Molecular Dynamics simulations of each protein and the stability of the fragment is ranked according to the frequency it is found within rigid-like domains.  Rigidity of the fragments can vary, as can the sharpness of the demarcations between adjacent fragments. Fragments do not preferentially correspond to secondary structure elements strongly indicating that secondary structure elements do not in general correspond to motional units.

Peptide conformations and protein folding

Understanding protein folding is one of the grand challenges of modern biology. It is also a critical test of our ability to accurately model interactions in protein systems. The group participates in an EC TMR network on protein folding co-ordinated by Dr. Ruud Scheek as well having projects funded by the NWO. Currently, it is not possible to directly simulate the folding of complete proteins using realistic conditions. Nevertheless, the last years has witnessed dramatic progress in the de novo folding of small peptides. In several cases we have been able to reversibly fold small peptides (~10 a.a.)  from arbitrary starting structures under native conditions with experimental accuracy.

Research on folding is conducted at multiple levels.  As part of the folding TMR network Dr. Danilo Roccatano has worked to develop new molecular dynamics (MD) methodologies to study the mechanism of folding/unfolding processes in proteins. He has used essential dynamics (ED) techniques to explore the unfolding/folding pathways of peptides and small proteins. The aim of this work is to obtain information in regard to the evolution of the non-bonded interactions during initial stages of the (un)folding process from MD simulations that can be used to efficiently drive more extensive simulations of the folding/unfolding process. By considering only those degrees of freedom critical to the folding the conformational space that must be searched can be greatly restricted.  To test these concepts studies are being performed using peptides that form simple motives in solution (e.g. beta-hairpins).

Other projects concern the simulation of the stability and de novo folding of small peptides is a variety of environments.  The structural and dynamical behaviour of the 41-56 beta-hairpin from the protein G B1 domain (GB1) in water has been investigated to determine the stability of this peptide in view of its possible role as a nucleation site for protein folding. Simulations of the wild type at different temperatures and of mutants of the peptide have been performed. The peptide adopts a series of conformations that are stable from 2 to > 10 ns dependent on the temperature. Although the peptide does not adopt the same conformation as found in the crystal structure the GB1 protein the predicted conformations are hairpin-like and are consistent with available experimental data on the isolated peptide. The simulations of different mutants verified the importance of the hydrophobic core region in stabilising the peptide.  Dr. Giorgio Colombo together with Patricia Soto is studying the folding and stability Betanova, which forms in solution a beta-hairpin motifs. Betanova and a series of related peptides were designed and characterised by Dr. Luis. Serrano's group at EMBL in Heidelberg and the project is in association with the Folding TMR network.

Last modified:04 February 2020 1.16 p.m.