Unlabelled: Chromatin organization is essential for DNA packaging and gene regulation in eukaryotic genomes. While significant progresses have been made, the exact atomistic arrangement of nucleosomes remains controversial. Using a well-calibrated residue-level coarse-grained model and advanced dynamics modeling techniques, particularly the non-Markovian dynamics model, we map the free energy landscape of tetra-nucleosome systems, identify both metastable conformations and intermediate states in folding pathways, and quantify the folding kinetics.
View Article and Find Full Text PDFTargeted protein degradation (TPD) is emerging as a promising therapeutic approach for cancer and other diseases, with an increasing number of programs demonstrating its efficacy in human clinical trials. One notable method for TPD is Proteolysis Targeting Chimeras (PROTACs) that selectively degrade a protein of interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize a warhead-linker-ligand architecture to bring the POI (bound to the warhead) and the E3 ligase (bound to the ligand) into proximity.
View Article and Find Full Text PDFMarkov state models (MSMs) have proven valuable in studying dynamics of protein conformational changes via statistical analysis of molecular dynamics (MD) simulations. In MSMs, the complex configuration space is coarse-grained into conformational states, with dynamics modeled by a series of Markovian transitions among these states at discrete lag times. Constructing the Markovian model at a specific lag time necessitates defining states that circumvent significant internal energy barriers, enabling internal dynamics relaxation within the lag time.
View Article and Find Full Text PDFMarkov state models (MSMs) have proven valuable in studying the dynamics of protein conformational changes via statistical analysis of molecular dynamics simulations. In MSMs, the complex configuration space is coarse-grained into conformational states, with dynamics modeled by a series of Markovian transitions among these states at discrete lag times. Constructing the Markovian model at a specific lag time necessitates defining states that circumvent significant internal energy barriers, enabling internal dynamics relaxation within the lag time.
View Article and Find Full Text PDFProtein conformational changes play crucial roles in their biological functions. In recent years, the Markov State Model (MSM) constructed from extensive Molecular Dynamics (MD) simulations has emerged as a powerful tool for modeling complex protein conformational changes. In MSMs, dynamics are modeled as a sequence of Markovian transitions among metastable conformational states at discrete time intervals (called lag time).
View Article and Find Full Text PDFThe generalized master equation (GME) provides a powerful approach to study biomolecular dynamics via non-Markovian dynamic models built from molecular dynamics (MD) simulations. Previously, we have implemented the GME, namely the quasi Markov State Model (qMSM), where we explicitly calculate the memory kernel and propagate dynamics using a discretized GME. qMSM can be constructed with much shorter MD trajectories than the MSM.
View Article and Find Full Text PDFUncovering slow collective variables (CVs) of self-assembly dynamics is important to elucidate its numerous kinetic assembly pathways and drive the design of novel structures for advanced materials through the bottom-up approach. However, identifying the CVs for self-assembly presents several challenges. First, self-assembly systems often consist of identical monomers, and the feature representations should be invariant to permutations and rotational symmetries.
View Article and Find Full Text PDFConformational changes (i.e., dynamic transitions between pairs of conformational states) play important roles in many chemical and biological processes.
View Article and Find Full Text PDFMutations in protein phosphatase 2A (PP2A) are connected to intellectual disability and cancer. It has been hypothesized that these mutations might disrupt the autoinhibition and phosphorylation-induced activation of PP2A. Since they are located far from both the active and substrate binding sites, it is unclear how they exert their effect.
View Article and Find Full Text PDFThe 3D reference interaction site model (3DRISM) provides an efficient grid-based solvation model to compute the structural and thermodynamic properties of biomolecules in aqueous solutions. However, it remains challenging for existing 3DRISM methods to correctly predict water distributions around negatively charged solute molecules. In this paper, we first show that this challenge is mainly due to the orientation of water molecules in the first solvation shell of the negatively charged solute molecules.
View Article and Find Full Text PDFAmidst the development of photoelectrochemical (PEC) CO conversion toward practical application, the production of high-value chemicals beyond C compounds under mild conditions is greatly desired yet challenging. Here, through rational PEC device design by combining Au-loaded and N-doped TiO plate nanoarray photoanode with Zn-doped CuO dark cathode, efficient conversion of CO to CHCOOH has been achieved with an outstanding Faradaic efficiency up to 58.1% (91.
View Article and Find Full Text PDFTransition-metal single-atom catalysts present extraordinary activity per metal atomic site, but suffer from low metal-atom densities (typically less than 5 wt% or 1 at.%), which limits their overall catalytic performance. Here we report a general method for the synthesis of single-atom catalysts with high transition-metal-atom loadings of up to 40 wt% or 3.
View Article and Find Full Text PDFNitrogen fixation in a simulated natural environment (i.e., near ambient pressure, room temperature, pure water, and incident light) would provide a desirable approach to future nitrogen conversion.
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