A5054621660- Protein Structure and Dynamics
- Spectroscopy and Quantum Chemical Studies
- Connexins and lens biology
- Advanced Electron Microscopy Techniques and Applications
- Cell Image Analysis Techniques
- Enzyme Structure and Function
- Gene Regulatory Network Analysis
- Mass Spectrometry Techniques and Applications
- Single-cell and spatial transcriptomics
- Advanced X-ray Imaging Techniques
- Advanced NMR Techniques and Applications
- RNA Research and Splicing
- Cellular Mechanics and Interactions
- bioluminescence and chemiluminescence research
- Machine Learning in Materials Science
- Lipid Membrane Structure and Behavior
- Advanced Biosensing Techniques and Applications
- Evolution and Genetic Dynamics
- Advanced Fluorescence Microscopy Techniques
- Rheology and Fluid Dynamics Studies
- Model Reduction and Neural Networks
- Advanced Thermodynamics and Statistical Mechanics
- DNA and Nucleic Acid Chemistry
- Molecular spectroscopy and chirality
- Simulation Techniques and Applications
Oregon Health & Science University
2018-2024
University of Oregon
2013-2017
University of Wisconsin–Milwaukee
2017
The weighted ensemble (WE) family of methods is one several statistical mechanics-based path sampling strategies that can provide estimates key observables (rate constants and pathways) using a fraction the time required by direct simulation such as molecular dynamics or discrete-state stochastic algorithms. WE oversee numerous parallel trajectories intermittent overhead operations at fixed intervals, enabling facile interoperability with any engine. Here, we report on major upgrades to...
Abstract Gap junctions establish direct pathways for cells to transfer metabolic and electrical messages. The local lipid environment is known affect the structure, stability intercellular channel activity of gap junctions; however, molecular basis these effects remains unknown. Here, we incorporate native connexin-46/50 (Cx46/50) channels into a dual nanodisc system, mimicking cell-to-cell junction. Structural characterization by CryoEM reveals lipid-induced stabilization channel, resulting...
Despite the development of massively parallel computing hardware including inexpensive graphics processing units (GPUs), it has remained infeasible to simulate folding atomistic proteins at room temperature using conventional molecular dynamics (MD) beyond microsecond scale. Here, we report atomistic, implicitly solvated protein systems with times τ ranging from ∼10 μs ∼100 ms weighted ensemble (WE) strategy in combination GPU computing. Starting an initial structure or set structures, WE...
The weighted ensemble (WE) simulation strategy provides unbiased sampling of nonequilibrium processes, such as molecular folding or binding, but the extraction rate constants relies on characterizing steady-state behavior. Unfortunately, WE simulations sufficiently complex systems will not relax to steady state observed times. Here, we show that a postsimulation clustering configurations into "microbins" using methods developed in Markov State Model (MSM) community can yield kinetics from...
Structural and thermodynamic consistency of coarse-graining models across multiple length scales is essential for the predictive role multi-scale modeling molecular dynamic simulations that use mesoscale descriptions. Our approach a coarse-grained model based on integral equation theory, which can represent polymer chains at variable levels chemical details. The analytical depends parameters system under study, as well direct correlation function in k --> 0 limit, c0. A numerical solution to...
Myotonic dystrophy type 2 is a genetic neuromuscular disease caused by the expression of expanded CCUG repeat RNAs from non-coding region CCHC-type zinc finger nucleic acid-binding protein (CNBP) gene. These repeats bind and sequester family RNA-binding proteins known as Muscleblind-like 1, 2, 3 (MBNL1, MBNL2, MBNL3), sequestration plays significant role in pathogenicity. MBNL are alternative splicing regulators that to consensus RNA sequence YGCY (Y = pyrimidine). This found toxic (CCUG...
Quantification of the temporal sequence molecular behavior in live individual cells holds promise for improving causal and mechanistic models cell biology. In recent years, different methods inferring labeling from microscopy data have been developed, especially context "virtual pathology", but less effort has directed to single-cell dynamics live-cell imaging. We demonstrate that phase-contrast imaging MCF10A cells, without data, is predictive dynamical, cell-cycle reporter Human DNA...
The microenvironment surrounding cells plays a critical role in determining cellular phenotype. Key components of the include diverse milieu ligands and cytokines bind cell surface receptors to initiate changes molecular programs. While responses extracellular signals have been extensively studied isolation, little is known about effects combinations on phenotypic transcriptional responses. In this study, we used coordinated approach systematically investigate combinatorial Oncostatin M...
Abstract Time-lapse imaging is a powerful approach to gain insight into the dynamic responses of cells, but quantitative analysis morphological changes over time remains challenging. Here, we exploit concept “trajectory embedding” analyze cellular behavior using feature trajectory histories—that is, multiple points simultaneously, rather than more common practice examining courses in single timepoint (snapshot) features. We apply this live-cell images MCF10A mammary epithelial cells after...
CUG repeat expansions in the 3′ UTR of dystrophia myotonica protein kinase (DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein–RNA aggregates. Structural studies demonstrate that can form A-form helices, suggesting secondary structure could be important pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2′-O-methylation to determine...
Weighted ensemble (WE) is an enhanced sampling method based on periodically replicating and pruning trajectories generated in parallel. WE has grown increasingly popular for computational biochemistry problems due, part, to improved hardware accessible software implementations. Algorithmic analytical improvements have played important role, progress accelerated recent years. Here, we discuss elaborate the from a mathematical perspective, highlighting results that enhance efficiency. The...
We utilize a multiscale approach where molecular dynamic simulations are performed to obtain quantitative structural averages used as input coarse-grained Langevin equation for protein dynamics, which can be solved analytically. The describes proteins fundamentally semiflexible objects collapsed into the free energy well representing folded state. normal-mode analytical solution this naturally separates global modes describing fully anisotropic tumbling of macromolecule whole and internal...
The biological properties of proteins are uniquely determined by their structure and dynamics. A protein in solution populates a structural ensemble metastable configurations around the global fold. From overall rotation to local fluctuations, dynamics can cover several orders magnitude time scales. We propose simulation-free coarse-grained approach which utilizes knowledge important folded states predict This is based upon Langevin Equation for Protein Dynamics (LE4PD), formalism...
Extracellular signals induce changes to molecular programs that modulate multiple cellular phenotypes, including proliferation, motility, and differentiation status. The connection between dynamically adapting phenotypic states the define them is not well understood. Here we develop data-driven models of single-cell responses extracellular stimuli by linking gene transcription levels "morphodynamics" - in cell morphology motility observable time-lapse image data. We adopt a dynamics-first...
The biological function of proteins is encoded in their structure and expressed through the mediation dynamics. This paper presents a study on correlation between local fluctuations, binding, for two sample proteins, starting from Langevin Equation Protein Dynamics (LE4PD). LE4PD microscopic residue-specific coarse-grained approach to protein dynamics, which starts static structural ensemble predicts dynamics analytically. It has been shown be accurate its prediction NMR relaxation...
We investigate the universal scaling of protein fluctuation dynamics with a site-specific diffusive model motion, which predicts an initial subdiffusive regime in configurational relaxation. The long-time proteins is controlled by activated regime. argue that hierarchical free energy barriers set time scales biological processes and establish upper limit to size single domains. find it compelling behavior for close agreement Kardar-Parisi-Zhang exponents.
Probability currents are fundamental in characterizing the kinetics of non-equilibrium processes. Notably, steady-state current $J_{ss}$ for a source-sink system can provide exact mean-first-passage time (MFPT) transition from source to sink. Because transient behavior is quantified some modern path sampling approaches, such as "weighted ensemble" strategy, there strong motivation determine bounds on -- and hence MFPT evolves time. Here we show that bounded above below by maximum minimum,...
Despite the development of massively parallel computing hardware including inexpensive graphics processing units (GPUs), it has remained infeasible to simulate folding atomistic proteins at room temperature using conventional molecular dynamics (MD) beyond µs scale. Here we report atomistic, implicitly solvated protein systems with times τ f ranging from ∼100 ∼1s weighted ensemble (WE) strategy in combination GPU computing. Starting an initial structure or set structures, WE organizes...
Abstract Gap junctions establish direct pathways for connected cells and tissues to transfer metabolic electrical messages 1 . The local lipid environment is known affect the structure, stability intercellular channel activity of gap 2-5 ; however, molecular basis these effects remains unknown. To gain insight toward how interact with their membrane environment, we used nanodisc technology incorporate native connexin-46/50 (Cx46/50) channels into a dual system, closely mimicking cell-to-cell...
We present two algorithms by which a set of short, unbiased trajectories can be iteratively reweighted to obtain various observables. The first algorithm estimates the stationary (steady state) distribution system reweighting based on average probability in each state. applies equilibrium or non-equilibrium steady states, exploiting `left' stationarity under dynamics -- i.e., discrete setting, when column vector probabilities is multiplied transition matrix expressed as left stochastic...