Multiscale characterization of protein conformational ensembles

Abstract

We propose a multiscale exploration method to characterize the conformational space populated by a protein at equilibrium. The method efficiently obtains a large set of equilibrium conformations in two stages: first exploring the entire space at a coarse-grained level of detail, then narrowing a refined exploration to selected low-energy regions. The coarse-grained exploration periodically adds all-atom detail to selected conformations to ensure that the search leads to regions which maintain low energies in all-atom detail. The second stage reconstructs selected low-energy coarse-grained conformations in all-atom detail. A low-dimensional energy landscape associated with all-atom conformations allows focusing the exploration to energy minima and their conformational ensembles. The lowest energy ensembles are enriched with additional all-atom conformations through further multiscale exploration. The lowest energy ensembles obtained from the application of the method to three different proteins correctly capture the known functional states of the considered systems.

Dynamical network of residue–residue contacts reveals coupled allosteric effects in recognition, catalysis, and mutation

“…A contact is defined to have formed between two residues if the distance between any of their heavy atoms is within a cutoff of 4.5 Å during the simulation. It is common to use such cutoff values in coarse-grained representation of protein structures (36)(37)(38) and evaluation of protein contacts (39,40). A contact receives a value of either 1 when formed or 0 when the contact is broken.…”

Understanding the challenges of protein flexibility in drug design

“…Instead, building a compact ensemble of representative protein conformations, as in ensemble docking, can be a useful preprocessing step. As this is done only once, this can involve more sophisticated and computationally-expensive approaches to sample large-scale conformational changes [36], [140]- [144]. Additionally, selective docking can be used for local refinement of the binding mode for each ligand in the dataset.…”

Relating Protein Structure and Function Through a Bijection and Its Implications on Protein Structure Prediction

“…The assembly of such substructures is determined by the energy potential and the conformation searching strategy. There are also multi-scale methods, like those of Cecilia Clementi, which change the resolution of the model depending on the questions that want to be asked of the protein (Shehu et al, 2009). …”