Binding-and-Folding Recognition of an Intrinsically Disordered Protein Using Online Learning Molecular Dynamics.

Intrinsically disordered proteins participate in many biological processes by folding upon binding to other proteins. However, coupled folding and binding processes are not well understood from an atomistic point of view. One of the main questions is whether folding occurs prior to or after binding. Here we use a novel, unbiased, high-throughput adaptive sampling approach to reconstruct the binding and folding between the disordered transactivation domain of c-Myb and the KIX domain of the CREB-binding protein. The reconstructed long-term dynamical process highlights the binding of a short stretch of amino acids on c-Myb as a folded α-helix. Leucine residues, especially Leu298-Leu302, establish initial native contacts that prime the binding and folding of the rest of the peptide, with a mixture of conformational selection on the N-terminal region with an induced fit of the C-terminal.

EvAM-Tools: tools for evolutionary accumulation and cancer progression models.

SUMMARY: EvAM-Tools is an R package and web application that provides a unified interface to state-of-the-art cancer progression models and, more generally, evolutionary models of event accumulation. The output includes, in addition to the fitted models, the transition (and transition rate) matrices between genotypes and the probabilities of evolutionary paths. Generation of random cancer progression models is also available. Using the GUI in the web application, users can easily construct models (modifying directed acyclic graphs of restrictions, matrices of mutual hazards or specifying genotype composition), generate data from them (with user-specified observational/genotyping error) and analyze the data. AVAILABILITY AND IMPLEMENTATION: Implemented in R and C; open source code available under the GNU Affero General Public License v3.0 at https://github.com/rdiaz02/EvAM-Tools. Docker images freely available from https://hub.docker.com/u/rdiaz02. Web app freely accessible at https://iib.uam.es/evamtools. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Author Correction: Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Small Molecule Modulation of Intrinsically Disordered Proteins Using Molecular Dynamics Simulations.

The extreme dynamic behavior of intrinsically disordered proteins hinders the development of drug-like compounds capable of modulating them. There are several examples of small molecules that specifically interact with disordered peptides. However, their mechanisms of action are still not well understood. Here, we use extensive molecular dynamics simulations combined with adaptive sampling algorithms to perform free ligand binding studies in the context of intrinsically disordered proteins. We tested this approach in the system composed by the D2 sub-domain of the disordered protein p27 and the small molecule SJ403. The results show several protein-ligand bound states characterized by the establishment of a loosely oriented interaction mediated by a limited number of contacts between the ligand and critical residues of p27. Finally, protein conformations in the bound state are likely to be explored by the isolated protein too, therefore supporting a model where the addition of the small molecule restricts the available conformational space.

Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations.

The exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior. In particular, the emergence of partially ordered states has not been explored in depth. The experimental characterization of such partially ordered states remains elusive due to their transient nature. Molecular dynamics mitigates this limitation thanks to its capability to explore biologically relevant timescales while retaining atomistic resolution. Here, millisecond unbiased molecular dynamics simulations were performed in the exemplar N-terminal region of p53. In combination with state-of-the-art Markov state models, simulations revealed the existence of several partially ordered states accounting for [Formula: see text] 40% of the equilibrium population. Some of the most relevant states feature helical conformations similar to the bound structure of p53 to Mdm2, as well as novel [Formula: see text]-sheet elements. This highlights the potential complexity underlying the energy surface of intrinsically disordered proteins.

AdaptiveBandit: A Multi-armed Bandit Framework for Adaptive Sampling in Molecular Simulations.

Sampling from the equilibrium distribution has always been a major problem in molecular simulations due to the very high dimensionality of the conformational space. Over several decades, many approaches have been used to overcome the problem. In particular, we focus on unbiased simulation methods such as parallel and adaptive sampling. Here, we recast adaptive sampling schemes on the basis of multi-armed bandits and develop a novel adaptive sampling algorithm under this framework, AdaptiveBandit. We test it on multiple simplified potentials and in a protein folding scenario. We find that this framework performs similarly to or better than previous methods in every type of test potential. Furthermore, it provides a novel framework to develop new sampling algorithms with better asymptotic characteristics.