Probing Protein Aggregation Using the Coarse-Grained UNRES Force Field.

Protein aggregation is the cause of many, often lethal, diseases, including the Alzheimer's, Parkinson's, and Huntington's diseases, and familial amyloidosis. Theoretical investigation of the mechanism of this process, including the structures of the oligomeric intermediates which are the most toxic, is difficult because of long time scale of aggregation. Coarse-grained models, which enable us to extend the simulation time scale by three or more orders of magnitude, are, therefore, of great advantage in such studies.

Investigation of Phosphorylation-Induced Folding of an Intrinsically Disordered Protein by Coarse-Grained Molecular Dynamics.

Apart from being the most common mechanism of regulating protein function and transmitting signals throughout the cell, phosphorylation has an ability to induce disorder-to-order transition in an intrinsically disordered protein. In particular, it was shown that folding of the intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can be induced by multisite phosphorylation. Here, the principles that govern the folding of phosphorylated 4E-BP2 (pT37pT46 4E-BP2) are investigated by analyzing canonical and replica exchange molecular dynamics trajectories, generated with the coarse-grained united-residue force field, in terms of local and global motions and the time dependence of formation of contacts between Cs of selected pairs of residues.

Dynamic and conformational switching in proteins.

Using bioinformatic methods for treating protein dynamics, developed in earlier work, we study the relationship between sequence mobility and dynamics in proteins. It is shown that sequence mobility drives a transition between two dynamic regimes in proteins, and that the specific details of this transition differ qualitatively between α-helical proteins and those in other structural classes. We examine the possibility that conformational switching is related to dynamic switching, by considering a specific system of sequences which exhibit the switching phenomenon.

The structure of protein dynamic space.

We use a bioinformatic description of amino acid dynamic properties, based on residue-specific average B factors, to construct a dynamics-based, large-scale description of a space of protein sequences. We examine the relationship between that space and an independently constructed, structure-based space comprising the same sequences. It is demonstrated that structure and dynamics are only moderately correlated.

Curvature and Torsion of Protein Main Chain as Local Order Parameters of Protein Unfolding.

Thermal protein unfolding resembles a global (two-state) phase transition. At the local scale, protein unfolding is, however, heterogeneous and probe dependent. Here, we consider local order parameters defined by the local curvature and torsion of the protein main chain.