Development of P450-BM3 using molecular dynamics simulations- A tribute to the late Professor Hideaki Yamada

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Enhanced and effective conformational sampling of protein molecular systems for their free energy landscapes

Protein folding and protein–ligand docking have long persisted as important subjects in biophysics. Using multicanonical molecular dynamics (McMD) simulations with realistic expressions, i.e., all-atom protein models and an explicit solvent, free-energy landscapes have been computed for several systems, such as the folding of peptides/proteins composed of a few amino acids up to nearly 60 amino-acid residues, protein–ligand interactions, and coupled folding and binding of intrinsically disordered proteins. Recent progress in conformational sampling and its applications to biophysical systems are reviewed in this report, including descriptions of several outstanding studies. In addition, an algorithm and detailed procedures used for multicanonical sampling are presented along with the methodology of adaptive umbrella sampling. Both methods control the simulation so that low-probability regions along a reaction coordinate are sampled frequently. The reaction coordinate is the potential energy for multicanonical sampling and is a structural identifier for adaptive umbrella sampling. One might imagine that this probability control invariably enhances conformational transitions among distinct stable states, but this study examines the enhanced conformational sampling of a simple system and shows that reasonably well-controlled sampling slows the transitions. This slowing is induced by a rapid change of entropy along the reaction coordinate. We then provide a recipe to speed up the sampling by loosening the rapid change of entropy. Finally, we report all-atom McMD simulation results of various biophysical systems in an explicit solvent

Exhaustive sampling of intrinsically disordered protein docking conformation with ALSD simulation

We tried to predict docking structures of a complex system of an intrinsically disordered protein (IDP) with high structural flexibility and the receptor protein using Adaptive Lambda Square Dynamics (ALSD) method, which is a molecular dynamics (MD) simulation to efficiently search conformations of biomolecules. Conventionally, since docking pose search calculations mostly treat conformations of proteins and the substrates as rigid bodies, it is difficult to apply these methods to IDPs, which do not have specific conformations. In this study, we considered conformational changes of proteins and substrates and performed an exhaustive conformational search for their docking poses. Because the conformational degrees of freedom of this system are much larger than those of systems to which ALSD has been successfully applied so far, the docking structure observed in the NMR models could not be reproduced within the project period. However, this study could clarify a specific problem occurring in conformation sampling of a system with high degrees of freedom and suggested a direction to improve ALSD

Simulation systems used and distribution of contact surface area (CSA) between the H3 tail and DNA in an obtained ensemble.

<p>(A) The system was prepared based on two nucleosome crystal structures, 1KX5 and 1ZBB. The linker DNA was extended by 10 bp from that of 1KX5 using the DNA structure of 1ZBB as a reference. Only atoms immersed within a water sphere centered at the root of the H3 tail (a nitrogen atom in the 40th residue) were considered in the simulations to reduce computational costs. All simulations were performed within the water sphere boundary. H3 histone tail, DNA, and histone core regions are shown in magenta, orange and green, respectively. (B) Distribution of CSA between the H3 tail and DNA is plotted as a function of the scaling factor λ for ALSD. See <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004788#pcbi.1004788.s001" target="_blank">S1 Fig</a> for the K14ac H3 tail.</p

Differences in the spatial distributions between the unacetylated and K14ac systems.

<p>Differences in the H3 tails and DNA are shown in the upper and lower panels, respectively. Blue and red contour maps show spatial regions preferred in the unacetylated and K14ac system, respectively. The coloring of the molecules and the nucleosome model are the same as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004788#pcbi.1004788.g001" target="_blank">Fig 1</a>.</p

H3 Histone Tail Conformation within the Nucleosome and the Impact of K14 Acetylation Studied Using Enhanced Sampling Simulation

<div><p>Acetylation of lysine residues in histone tails is associated with gene transcription. Because histone tails are structurally flexible and intrinsically disordered, it is difficult to experimentally determine the tail conformations and the impact of acetylation. In this work, we performed simulations to sample H3 tail conformations with and without acetylation. The results show that irrespective of the presence or absence of the acetylation, the H3 tail remains in contact with the DNA and assumes an α-helix structure in some regions. Acetylation slightly weakened the interaction between the tail and DNA and enhanced α-helix formation, resulting in a more compact tail conformation. We inferred that this compaction induces unwrapping and exposure of the linker DNA, enabling DNA-binding proteins (e.g., transcription factors) to bind to their target sequences. In addition, our simulation also showed that acetylated lysine was more often exposed to the solvent, which is consistent with the fact that acetylation functions as a post-translational modification recognition site marker.</p></div

Impact of K14ac on H3 tail conformation.

<p>(A) Average α-helical content ratio with the standard error for each residue of unacetylated and K14ac H3 tails. The error bars represent the standard errors calculated from 256 independent trajectories. (B) Rg distributions for unacetylated and K14ac H3 tails.</p