Additional file 1 of Pan-cancer landscape of aberrant DNA Methylation across childhood Cancers: Molecular Characteristics and Clinical relevance

Additional file 1: Supplementary Table 1-7: Supplementary Table 1. Characteristics of methylation and gene expression data sets used in this study. Supplementary Table 2. Numbers of differentially methylated CpG sites identified in pediatric cancers. Supplementary Table 3. The list of SDMCs. Supplementary Table 4. Differentially methylated SDMCs in adult cancers. Supplementary Table 5. Co-location and enrichment of SDMCs in Genomic features. Supplementary Table 6. Associations between SDMCs and gene transcription. Supplementary Table 7. Pathway enrichment analysis of SDMCs

Additional file 2 of Pan-cancer landscape of aberrant DNA Methylation across childhood Cancers: Molecular Characteristics and Clinical relevance

Additional file 2: Supplementary Figure 1. A heatmap of correlations between SDMC methylation and gene transcription in adult cancers, colored by Pearson’s r. Only three SDMCs mapped to gene promoters are investigated. Associations with FDR values greater than 0.05 are shown as whit

Dynamics Sampling in Transition Pathway Space

The minimum energy pathway contains important information describing the transition between two states on a potential energy surface (PES). Chain-of-states methods were developed to efficiently calculate minimum energy pathways connecting two stable states. In the chain-of-states framework, a series of structures are generated and optimized to represent the minimum energy pathway connecting two states. However, multiple pathways may exist connecting two existing states and should be identified to obtain a full view of the transitions. Therefore, we developed an enhanced sampling method, named as the direct pathway dynamics sampling (DPDS) method, to facilitate exploration of a PES for multiple pathways connecting two stable states as well as addition minima and their associated transition pathways. In the DPDS method, molecular dynamics simulations are carried out on the targeting PES within a chain-of-states framework to directly sample the transition pathway space. The simulations of DPDS could be regulated by two parameters controlling distance among states along the pathway and smoothness of the pathway. One advantage of the chain-of-states framework is that no specific reaction coordinates are necessary to generate the reaction pathway, because such information is implicitly represented by the structures along the pathway. The chain-of-states setup in a DPDS method greatly enhances the sufficient sampling in high-energy space between two end states, such as transition states. By removing the constraint on the end states of the pathway, DPDS will also sample pathways connecting minima on a PES in addition to the end points of the starting pathway. This feature makes DPDS an ideal method to directly explore transition pathway space. Three examples demonstrate the efficiency of DPDS methods in sampling the high-energy area important for reactions on the PES

Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery

<div><p>Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Châtelier’s principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery.</p></div

Average entropic response from each residue in all RRS simulations.

<p>Average entropic response from each residue in all RRS simulations.</p

Distribution of unperturbed states projected onto a 2D surface using two PC1 modes.

<p>Only one set of 30 ns trajectories are used for sake of consistency with RRS simulations.</p

Heat maps of individual residue entropic contribution under rigid residue perturbation for unbound (left) and bound (right) states.

<p>The entropic contribution from each residue in unperturbed simulations (with index as 0 in both plots) is set as reference.</p

Key residues recognized based on protein entropic response to rigid body perturbation.

<p>Key residues recognized based on protein entropic response to rigid body perturbation.</p

Distributions of density of states for unperturbed unbound and bound states.

<p>Distributions of density of states for unperturbed unbound and bound states.</p

Key residues for PDZ2 allostery upon RA-GEF2 peptide binding from NMR study [72].

<p>Key residues for PDZ2 allostery upon RA-GEF2 peptide binding from NMR study [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004893#pcbi.1004893.ref072" target="_blank">72</a>].</p