Investigations of the Underlying Mechanisms of HIF-1{\alpha} and CITED2 Binding to TAZ1

The TAZ1 domain of CREB binding protein is crucial for transcriptional regulation and recognizes multiple targets. The interactions between TAZ1 and its specific targets are related to the cellular hypoxic negative feedback regulation. Previous experiments reported that one of the TAZ1 targets CITED2 is an efficient competitor of another target HIF-1{\alpha}. Here by developing the structure-based models of TAZ1 complexes we have uncovered the underlying mechanisms of the competitions between HIF-1{\alpha} and CITED2 binding to TAZ1. Our results are consistent with the experimental hypothesis on the competition mechanisms and the apparent affinity. In addition, the simulations prove the dominant position of forming TAZ1-CITED2 complex in both thermodynamics and kinetics. For thermodynamics, TAZ1-CITED2 is the lowest basin located on the free energy surface of binding in the ternary system. For kinetics, the results suggest that CITED2 binds to TAZ1 faster than HIF-1{\alpha}. Besides, the analysis of contact map and f values in this study will be helpful for further experiments on TAZ1 systems.Comment: 12 pages, 6 figure

Multi-Scaled Explorations of Binding-Induced Folding of Intrinsically Disordered Protein Inhibitor IA3 to its Target Enzyme

Biomolecular function is realized by recognition, and increasing evidence shows that recognition is determined not only by structure but also by flexibility and dynamics. We explored a biomolecular recognition process that involves a major conformational change – protein folding. In particular, we explore the binding-induced folding of IA3, an intrinsically disordered protein that blocks the active site cleft of the yeast aspartic proteinase saccharopepsin (YPrA) by folding its own N-terminal residues into an amphipathic alpha helix. We developed a multi-scaled approach that explores the underlying mechanism by combining structure-based molecular dynamics simulations at the residue level with a stochastic path method at the atomic level. Both the free energy profile and the associated kinetic paths reveal a common scheme whereby IA3 binds to its target enzyme prior to folding itself into a helix. This theoretical result is consistent with recent time-resolved experiments. Furthermore, exploration of the detailed trajectories reveals the important roles of non-native interactions in the initial binding that occurs prior to IA3 folding. In contrast to the common view that non-native interactions contribute only to the roughness of landscapes and impede binding, the non-native interactions here facilitate binding by reducing significantly the entropic search space in the landscape. The information gained from multi-scaled simulations of the folding of this intrinsically disordered protein in the presence of its binding target may prove useful in the design of novel inhibitors of aspartic proteinases

Folding and Binding of DPO4

This repository includes: (1) necessary files for setting up and running Gromacs (version 4.5.7 with PLUMED version 2.5.0) simulations on DPO4 folding and DNA-binding with coarse-grained structure-based models. (2) programs and scripts for performing WHAM and reweigthing WHAM for DPO4 REMD folding (3) programs and scripts for performing DPO4 kinetic folding simulations (4) programs and scripts for performing WHAM for DPO4-DNA umbrella sampling binding (5) programs and scripts for performing frequency-adaptive metadynamics (rate calculation matlab script can be found at JCTC, 2014, 10, 1420-1425) Please let me know if you have any question

Chromosome Dynamics in Cancerization and Reversion

This repository provides: (1) Essential files for performing the chromosome dynamics transitions between normal (IMR90) cell and cancer (A549) cell. Software undertaking the tasks are Gromacs (4.5.7) and Plumed (2.5.0). (2) Programs and scripts for analysi

Chromosome Dynamics in Cell Fate Decision Making

Gromacs 4.5.7 with PLUMED 2.5.0 to simulate the chromosome structural transitions among the ESC, normal and cancer cell

Quantifying the large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition of cell cycle

Cell cycle is known to be regulated by the underlying gene network. Chromosomes, which serve as the scaffold for gene expressions, undergo significant structural reorganizations during mitosis. Understanding the mechanism of the cell cycle from the chromosome structural perspective remains a grand challenge. In this study, we applied an integrated theoretical approach to investigate large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition. We observed that the chromosome structural expansion and adaptation of the structural asphericity do not occur synchronously and attributed this behaviour to the unique unloading sequence of the two types of condensins. Furthermore, we observed that the coherent motions between the chromosomal loci are primarily enhanced within the topologically associating domains (TADs) as cells progress to the G1 phase, suggesting that TADs can be considered as both structural and dynamical units for organizing the three-dimensional chromosome. Our analysis also reveals that the quantified pathways of chromosome structural reorganization during the mitosis-to-G1 phase transition exhibit high stochasticity at the single-cell level and show nonlinear behaviours in changing TADs and contacts formed at the long-range regions. Our findings offer valuable insights into large-scale chromosome structural dynamics after mitosis

The differences of thermodynamics and kinetics between rigid and flexible binding.

<p>(A) The free energy landscapes of rigid and flexible binding are plotted at the corresponding binding temperature . (B) The differences of kinetics, represented by the ratio of binding time between rigid and flexible binding, are plotted along the differences of intrinsic specificity between rigid and flexible binding.</p

Quantified folding energy landscapes with and without interfacial binding.

<p>Because the homodimer is formed by two identical chains, the folding properties of the two monomers for each homodimer are expected to be same.</p>a<p>“Ind” and “Eff” are the abbreviations for “Independent” and “Effective” folding, respectively.</p

The folding stability for folding with and without interfacial binding shown in (A) heat capacity curves and (B) free energy landscapes for Lambda Cro repressor (red) and Lambda repressor (blue).

<p>The solid and corresponding dotted lines represent isolated (independent) and dimeric (effective) folding respectively. Free energy landscapes are plotted at the isolated folding transition temperatures, which are calculated from the peaks of heat capacity curves for folding, respectively. Free energy is in reduced unit.</p