PACSAB Server: A Web-Based Tool for the Study of Aggregation and the Conformational Ensemble of Disordered and Folded Proteins.

We present in this article the PACSAB server, which is designed to provide information about the structural ensemble and interactions of both stable and disordered proteins to researchers in the field of molecular biology. The use of this tool does not require any computational skills as the user just needs to upload the structure of the protein to be studied; the server runs a simulation with the PACSAB model, a highly accurate coarse-grained model that is much more efficient than standard molecular dynamics for the exploration of the conformational space of multiprotein systems. The trajectories generated by the simulations based on this model reveal the propensity of the protein under study for aggregation, identify the residues playing a central role in the aggregation process, and reproduce the whole conformational space of disordered proteins.

Universal ion-transport descriptors and classes of inorganic solid-state electrolytes.

Solid-state electrolytes (SSEs) with high ion conductivity are pivotal for the development and large-scale adoption of green-energy conversion and storage technologies such as fuel cells, electrocatalysts and solid-state batteries. Yet, SSEs are extremely complex materials for which general rational design principles remain indeterminate. Here, we combine first-principles materials modelling, computational power and modern data analysis techniques to advance towards the solution of such a fundamental and technologically pressing problem.

Accurate Description of Protein-Protein Recognition and Protein Aggregation with the Implicit-Solvent-Based PACSAB Protein Model.

We used the PACSAB protein model, based on the implicit solvation approach, to simulate protein-protein recognition and study the effect of helical structure on the association of aggregating peptides. After optimization, the PACSAB force field was able to reproduce correctly both the correct binding interface in ubiquitin dimerization and the conformational ensemble of the disordered protein activator for hormone and retinoid receptor (ACTR). The PACSAB model allowed us to predict the native binding of ACTR with its binding partner, reproducing the refolding upon binding mechanism of the disordered protein.

Effect of the Water Model in Simulations of Protein-Protein Recognition and Association.

We study self-association of ubiquitin and the disordered protein ACTR using the most commonly used water models. We find that dissociation events are found only with TIP4P-EW and TIP4P/2005, while the widely used TIP3P water model produces straightforward aggregation of the molecules due to the absence of dissociation events. We also find that TIP4P/2005 is the only water model that reproduces the fast association/dissociation dynamics of ubiquitin and best identifies its binding surface.

Discrete Molecular Dynamics Approach to the Study of Disordered and Aggregating Proteins.

We present a refinement of the Coarse Grained PACSAB force field for Discrete Molecular Dynamics (DMD) simulations of proteins in aqueous conditions. As the original version, the refined method provides good representation of the structure and dynamics of folded proteins but provides much better representations of a variety of unfolded proteins, including some very large, impossible to analyze by atomistic simulation methods. The PACSAB/DMD method also reproduces accurately aggregation properties, providing good pictures of the structural ensembles of proteins showing a folded core and an intrinsically disordered region.

Residues Coevolution Guides the Systematic Identification of Alternative Functional Conformations in Proteins.

We present here a new approach for the systematic identification of functionally relevant conformations in proteins. Our fully automated pipeline, based on discrete molecular dynamics enriched with coevolutionary information, is able to capture alternative conformational states in 76% of the proteins studied, providing key atomic details for understanding their function and mechanism of action. We also demonstrate that, given its sampling speed, our method is well suited to explore structural transitions in a high-throughput manner, and can be used to determine functional conformational transitions at the entire proteome level.

PACSAB: Coarse-Grained Force Field for the Study of Protein-Protein Interactions and Conformational Sampling in Multiprotein Systems.

Molecular dynamics simulations of proteins are usually performed on a single molecule, and coarse-grained protein models are calibrated using single-molecule simulations, therefore ignoring intermolecular interactions. We present here a new coarse-grained force field for the study of many protein systems. The force field, which is implemented in the context of the discrete molecular dynamics algorithm, is able to reproduce the properties of folded and unfolded proteins, in both isolation, complexed forming well-defined quaternary structures, or aggregated, thanks to its proper evaluation of protein-protein interactions.

Exploration of conformational transition pathways from coarse-grained simulations.

Motivation: A new algorithm to trace conformational transitions in proteins is presented. The method uses discrete molecular dynamics as engine to sample protein conformational space. A multiple minima Go-like potential energy function is used in combination with several enhancing sampling strategies, such as metadynamics, Maxwell Demon molecular dynamics and essential dynamics.

Efficient Relaxation of Protein-Protein Interfaces by Discrete Molecular Dynamics Simulations.

Protein-protein interactions are responsible for the transfer of information inside the cell and represent one of the most interesting research fields in structural biology. Unfortunately, after decades of intense research, experimental approaches still have difficulties in providing 3D structures for the hundreds of thousands of interactions formed between the different proteins in a living organism. The use of theoretical approaches like docking aims to complement experimental efforts to represent the structure of the protein interactome.

Finding Conformational Transition Pathways from Discrete Molecular Dynamics Simulations.

We present a new method for estimating pathways for conformational transitions in macromolecules from the use of discrete molecular dynamics and biasing techniques based on a combination of essential dynamics and Maxwell-Demon sampling techniques. The method can work with high efficiency at different levels of resolution, including the atomistic one, and can help to define initial pathways for further exploration by means of more accurate atomistic molecular dynamics simulations. The method is implemented in a freely available Web-based application accessible at http://mmb.

Coarse-grained representation of protein flexibility. Foundations, successes, and shortcomings.

Flexibility is the key magnitude to understand the variety of functions of proteins. Unfortunately, its experimental study is quite difficult, and in fact, most experimental procedures are designed to reduce flexibility and allow a better definition of the structure. Theoretical approaches have become then the alternative but face serious timescale problems, since many biologically relevant deformation movements happen in a timescale that is far beyond the possibility of current atomistic models.

Protein flexibility from discrete molecular dynamics simulations using quasi-physical potentials.

We have applied all atoms discrete molecular dynamics (DMD) based on a quasi-physical potential to study the flexibility of an extended set of proteins for which atomistic MD simulations are available. The method uses pure physical potentials supplemented by information on secondary structure and despite its simplicity is able to reproduce with good accuracy the dynamics of proteins in solution. The method presents a clear improvement with respect to coarse-grained methods based on structure potentials and opens the possibility to explore dynamics of proteins out from the equilibrium and to trace conformational changes induced by interaction of proteins with both small and macromolecular ligands.

FlexServ: an integrated tool for the analysis of protein flexibility.

Summary: FlexServ is a web-based tool for the analysis of protein flexibility. The server incorporates powerful protocols for the coarse-grained determination of protein dynamics using different versions of Normal Mode Analysis (NMA), Brownian dynamics (BD) and Discrete Dynamics (DMD). It can also analyze user provided trajectories.

United-Atom Discrete Molecular Dynamics of Proteins Using Physics-Based Potentials.

We present a method for the efficient simulation of the equilibrium dynamics of proteins based on the well established discrete molecular dynamics algorithm, which avoids integration of Newton equations of motion at short time steps, allowing then the derivation of very large trajectories for proteins with a reduced computational cost. In the presented implementation we used an all heavy-atoms description of proteins, with simple potentials describing the conformational region around the experimental structure based on local physical interactions (covalent structure, hydrogen bonds, hydrophobic contacts, solvation, steric hindrance, and bulk dispersion interactions). The method shows a good ability to describe the flexibility of 33 diverse proteins in water as determined by atomistic molecular dynamics simulation and can be useful for massive simulation of proteins in crowded environments or for refinement of protein structure in large complexes.

Exploring the suitability of coarse-grained techniques for the representation of protein dynamics.

A systematic study of two coarse-grained techniques for the description of protein dynamics is presented. The two techniques exploit either Brownian or discrete molecular dynamics algorithms applied in the context of simple C(alpha)-C(alpha) potentials, like those used in coarse-grained normal mode analysis. Coarse-grained simulations of the flexibility of protein metafolds are compared to those computed with fully atomistic molecular dynamics simulations using state-of-the-art physical potentials and explicit solvent.