Towards gaining sight of multiscale events: utilizing network models and normal modes in hybrid methods.
Ontology highlight
ABSTRACT:
SUBMITTER: Krieger JM
PROVIDER: S-EPMC7666066 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Amyloid fibrils are thought to grow by a two-step dock-lock mechanism. However, previous simulations of fibril formation (i) overlook the bi-molecular nature of the docking step and obtain rates with first-order units, or (ii) superimpose the docked and locked states when computing the potential of mean force for association and thereby muddle the docking and locking steps. Here, we developed a simple microkinetic model with separate locking and docking steps and with the appropriate concentration dependences for each step. We constructed a simple model comprised of chiral dumbbells that retains qualitative aspects of fibril formation. We used rare events methods to predict separate docking and locking rate constants for the model. The rate constants were embedded in the microkinetic model, with the microkinetic model embedded in a population balance model for "bottom-up" multiscale fibril growth rate predictions. These were compared to "top-down" results using simulation data with the same model and multiscale framework to obtain maximum likelihood estimates of the separate lock and dock rate constants. We used the same procedures to extract separate docking and locking rate constants from experimental fibril growth data. Our multiscale strategy, embedding rate theories, and kinetic models in conservation laws should help to extract docking and locking rate constants from experimental data or long molecular simulations with correct units and without compromising the molecular description.
| S-EPMC8234428 | biostudies-literature
Project description:Vesicular transport driven by membrane trafficking systems conserved in eukaryotes is critical to cellular functionality and homeostasis. It is known that homotypic fusion and vacuole protein sorting (HOPS) and class C core endosomal vacuole tethering (CORVET) interact with Rab-GTPases and SNARE proteins to regulate vesicle transport, fusion, and maturation in autophagy and endocytosis pathways. In this study, we identified two novel "Hybrid" tethering complexes in mammalian cells in which one of the subunits of HOPS or CORVET is replaced with the subunit from the other. Substrates taken up by receptor-mediated endocytosis or pinocytosis were transported by distinctive pathways, and the newly identified hybrid complexes contributed to pinocytosis in the presence of HOPS, whereas receptor-mediated endocytosis was exclusively dependent on HOPS. Our study provides new insights into the molecular mechanisms of the endocytic pathway and the function of the vacuolar protein sorting-associated (VPS) protein family.
| S-EPMC10618185 | biostudies-literature
Project description:Due to the ongoing improvement in nanostructuring technology, ultrathin metallic nanofilms have recently gained substantial attention in plasmonics, e.g. as building blocks of metasurfaces. Typically, noble metals such as silver or gold are the materials of choice, due to their excellent optical properties, however they also possess some intrinsic disadvantages. Here, we introduce niobium nanofilms (~10 nm thickness) as an alternate plasmonic platform. We demonstrate functionality by depositing a niobium nanofilm on a plasmonic fiber taper, and observe a dielectric-loaded niobium surface-plasmon excitation for the first time, with a modal attenuation of only 3-4 dB/mm in aqueous environment and a refractive index sensitivity up to 15 μm/RIU if the analyte index exceeds 1.42. We show that the niobium nanofilm possesses bulk optical properties, is continuous, homogenous, and inert against any environmental influence, thus possessing several superior properties compared to noble metal nanofilms. These results demonstrate that ultrathin niobium nanofilms can serve as a new platform for biomedical diagnostics, superconducting photonics, ultrathin metasurfaces or new types of optoelectronic devices.
| S-EPMC4655396 | biostudies-other
Project description:BACKGROUND:The Institute for Healthcare Improvement defines an adverse event as an unintended physical injury resulting from or contributed to by medical care that requires additional monitoring, treatment, or hospitalization or that results in death. The majority of research has focused on adverse events from the provider's perspective. OBJECTIVE:The objective of this qualitative study was to describe patient perceptions on adverse events following surgery for pelvic floor disorders. STUDY DESIGN:Women representing the following 3 separate surgical populations participated in focus groups: (1) preoperative (women <12 weeks prior to surgery); (2) short-term postoperative (women up to 12 weeks after surgery); and (3) long-term postoperative (women 1-5 years after surgery). Deidentified transcripts of audio recordings were coded and analyzed with NVivo 10 software to identify themes, concepts, and adverse events. Women were asked to rank patient-identified and surgeon-identified adverse events in order of perceived severity. RESULTS:Eighty-one women participated in 12 focus groups. Group demographics were similar between groups, and all groups shared similar perspectives regarding surgical expectations. Women commonly reported an unclear understanding of their surgery and categorized adverse events such as incontinence, constipation, nocturia, and lack of improvement in sexual function as very severe, ranking these comparably with intensive care unit admissions or other major surgical complications. Women also expressed a sense of personal failure and shame if symptoms recurred. CONCLUSION:Women consider functional outcomes such as incontinence, sexual dysfunction, and recurrence of symptoms as severe adverse events and rate them as similar in severity to intensive care unit admissions and death.
| S-EPMC6351201 | biostudies-literature
Project description:In this article we review the key modeling tools available for simulating biomolecular systems. We consider recent developments and representative applications of mixed quantum mechanics/molecular mechanics (QM/MM), elastic network models (ENMs), coarse-grained molecular dynamics, and grid-based tools for calculating interactions between essentially rigid protein assemblies. We consider how the different length scales can be coupled, both in a sequential fashion (e.g. a coarse-grained or grid model using parameterization from MD simulations), and via concurrent approaches, where the calculations are performed together and together control the progression of the simulation. We suggest how the concurrent coupling approach familiar in the context of QM/MM calculations can be generalized, and describe how this has been done in the CHARMM macromolecular simulation package.
| S-EPMC6407689 | biostudies-literature
Project description:We present SEEKR2 (simulation-enabled estimation of kinetic rates version 2)─the latest iteration in the family of SEEKR programs for using multiscale simulation methods to computationally estimate the kinetics and thermodynamics of molecular processes, in particular, ligand-receptor binding. SEEKR2 generates equivalent, or improved, results compared to the earlier versions of SEEKR but with significant increases in speed and capabilities. SEEKR2 has also been built with greater ease of usability and with extensible features to enable future expansions of the method. Now, in addition to supporting simulations using NAMD, calculations may be run with the fast and extensible OpenMM simulation engine. The Brownian dynamics portion of the calculation has also been upgraded to Browndye 2. Furthermore, this version of SEEKR supports hydrogen mass repartitioning, which significantly reduces computational cost, while showing little, if any, loss of accuracy in the predicted kinetics.
| S-EPMC9277580 | biostudies-literature
Project description:BACKGROUND: Stochastic simulation of gene networks by Markov processes has important applications in molecular biology. The complexity of exact simulation algorithms scales with the number of discrete jumps to be performed. Approximate schemes reduce the computational time by reducing the number of simulated discrete events. Also, answering important questions about the relation between network topology and intrinsic noise generation and propagation should be based on general mathematical results. These general results are difficult to obtain for exact models. RESULTS: We propose a unified framework for hybrid simplifications of Markov models of multiscale stochastic gene networks dynamics. We discuss several possible hybrid simplifications, and provide algorithms to obtain them from pure jump processes. In hybrid simplifications, some components are discrete and evolve by jumps, while other components are continuous. Hybrid simplifications are obtained by partial Kramers-Moyal expansion [1-3] which is equivalent to the application of the central limit theorem to a sub-model. By averaging and variable aggregation we drastically reduce simulation time and eliminate non-critical reactions. Hybrid and averaged simplifications can be used for more effective simulation algorithms and for obtaining general design principles relating noise to topology and time scales. The simplified models reproduce with good accuracy the stochastic properties of the gene networks, including waiting times in intermittence phenomena, fluctuation amplitudes and stationary distributions. The methods are illustrated on several gene network examples. CONCLUSION: Hybrid simplifications can be used for onion-like (multi-layered) approaches to multi-scale biochemical systems, in which various descriptions are used at various scales. Sets of discrete and continuous variables are treated with different methods and are coupled together in a physically justified approach.
| S-EPMC2761401 | biostudies-other
Project description:Cross-entropy was introduced in 1996 to quantify the degree of asynchronism between two time series. In 2009, a multiscale cross-entropy measure was proposed to analyze the dynamical characteristics of the coupling behavior between two sequences on multiple scales. Since their introductions, many improvements and other methods have been developed. In this review we offer a state-of-the-art on cross-entropy measures and their multiscale approaches.
| S-EPMC7516475 | biostudies-literature
Project description:Proteins and other macromolecules have coupled dynamics over multiple time scales (from femtosecond to millisecond and beyond) that make resolving molecular dynamics challenging. We present an approach based on periodically decomposing the dynamics of a macromolecule into slow and fast modes based on a scalable coarse-grained normal mode analysis. A Langevin equation is used to propagate the slowest degrees of freedom while minimizing the nearly instantaneous degrees of freedom. We present numerical results showing that time steps of up to 1000 fs can be used, with real speedups of up to 200 times over plain molecular dynamics. We present results of successfully folding the Fip35 mutant of WW domain.
| S-EPMC4308582 | biostudies-literature
Project description:Nonlinear normal modes (NNMs) are widely used as a tool for understanding the forced responses of nonlinear systems. However, the contemporary definition of an NNM also encompasses a large number of dynamic behaviours which are not observed when a system is forced and damped. As such, only a few NNMs are required to understand the forced dynamics. This paper firstly demonstrates the complexity that may arise from the NNMs of a simple nonlinear system-highlighting the need for a method for identifying the significance of NNMs. An analytical investigation is used, alongside energy arguments, to develop an understanding of the mechanisms that relate the NNMs to the forced responses. This provides insight into which NNMs are pertinent to understanding the forced dynamics, and which may be disregarded. The NNMs are compared with simulated forced responses to verify these findings.
| S-EPMC5378240 | biostudies-literature