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Learning dynamical information from static protein and sequencing data.

ABSTRACT: Many complex processes, from protein folding to neuronal network dynamics, can be described as stochastic exploration of a high-dimensional energy landscape. Although efficient algorithms for cluster detection in high-dimensional spaces have been developed over the last two decades, considerably less is known about the reliable inference of state transition dynamics in such settings. Here we introduce a flexible and robust numerical framework to infer Markovian transition networks directly from time-independent data sampled from stationary equilibrium distributions. We demonstrate the practical potential of the inference scheme by reconstructing the network dynamics for several protein-folding transitions, gene-regulatory network motifs, and HIV evolution pathways. The predicted network topologies and relative transition time scales agree well with direct estimates from time-dependent molecular dynamics data, stochastic simulations, and phylogenetic trees, respectively. Owing to its generic structure, the framework introduced here will be applicable to high-throughput RNA and protein-sequencing datasets, and future cryo-electron microscopy (cryo-EM) data.

SUBMITTER: Pearce P

PROVIDER: S-EPMC6879630 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Learning dynamical information from static protein and sequencing data.

Pearce Philip P Woodhouse Francis G FG Forrow Aden A Kelly Ashley A Kusumaatmaja Halim H Dunkel Jörn J

Nature communications 20191126 1

Many complex processes, from protein folding to neuronal network dynamics, can be described as stochastic exploration of a high-dimensional energy landscape. Although efficient algorithms for cluster detection in high-dimensional spaces have been developed over the last two decades, considerably less is known about the reliable inference of state transition dynamics in such settings. Here we introduce a flexible and robust numerical framework to infer Markovian transition networks directly from ...[more]

PMID: 31772168

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Project description:BackgroundBedside monitors in the ICU routinely measure and collect patients' physiologic data in real time to continuously assess the health status of patients who are critically ill. With the advent of increased computational power and the ability to store and rapidly process big data sets in recent years, these physiologic data show promise in identifying specific outcomes and/or events during patients' ICU hospitalization.MethodsWe introduced a methodology designed to automatically extract information from continuous-in-time vital sign data collected from bedside monitors to predict if a patient will experience a prolonged stay (length of stay) on mechanical ventilation, defined as >4 d, in a pediatric ICU.ResultsContinuous-in-time vital signs information and clinical history data were retrospectively collected for 284 ICU subjects from their first 24 h on mechanical ventilation from a medical-surgical pediatric ICU at Boston Children's Hospital. Multiple machine learning models were trained on multiple subsets of these subjects to predict the likelihood that each of these subjects would experience a long stay. We evaluated the predictive power of our models strictly on unseen hold-out validation sets of subjects. Our methodology achieved model performance of >83% (area under the curve) by using only vital sign information as input, and performances of 90% (area under the curve) by combining vital sign information with subjects' static clinical data readily available in electronic health records. We implemented this approach on 300 independently trained experiments with different choices of training and hold-out validation sets to ensure the consistency and robustness of our results in our study sample. The predictive power of our approach outperformed recent efforts that used deep learning to predict a similar task.ConclusionsOur proposed workflow may prove useful in the design of scalable approaches for real-time predictive systems in ICU environments, exploiting real-time vital sign information from bedside monitors. (ClinicalTrials.gov registration NCT02184208.).

Project description:CONSPECTUS: The image is not the thing. Just as a pipe rendered in an oil painting cannot be smoked, quantum mechanical coupling pathways rendered on LCDs do not convey electrons. The aim of this Account is to examine some of our recent discoveries regarding biological electron transfer (ET) and transport mechanisms that emerge when one moves beyond treacherous static views to dynamical frameworks. Studies over the last two decades introduced both atomistic detail and macromolecule dynamics to the description of biological ET. The first model to move beyond the structureless square-barrier tunneling description is the Pathway model, which predicts how protein secondary motifs and folding-induced through-bond and through-space tunneling gaps influence kinetics. Explicit electronic structure theory is applied routinely now to elucidate ET mechanisms, to capture pathway interferences, and to treat redox cofactor electronic structure effects. Importantly, structural sampling of proteins provides an understanding of how dynamics may change the mechanisms of biological ET, as ET rates are exponentially sensitive to structure. Does protein motion average out tunneling pathways? Do conformational fluctuations gate biological ET? Are transient multistate resonances produced by energy gap fluctuations? These questions are becoming accessible as the static view of biological ET recedes and dynamical viewpoints take center stage. This Account introduces ET reactions at the core of bioenergetics, summarizes our team's progress toward arriving at an atomistic-level description, examines how thermal fluctuations influence ET, presents metrics that characterize dynamical effects on ET, and discusses applications in very long (micrometer scale) bacterial nanowires. The persistence of structural effects on the ET rates in the face of thermal fluctuations is considered. Finally, the flickering resonance (FR) view of charge transfer is presented to examine how fluctuations control low-barrier transport among multiple groups in van der Waals contact. FR produces exponential distance dependence in the absence of tunneling; the exponential character emerges from the probability of matching multiple vibronically broadened electronic energies within a tolerance defined by the rms coupling among interacting groups. FR thus produces band like coherent transport on the nanometer length scale, enabled by conformational fluctuations. Taken as a whole, the emerging context for ET in dynamical biomolecules provides a robust framework to design and interpret the inner workings of bioenergetics from the molecular to the cellular scale and beyond, with applications in biomedicine, biocatalysis, and energy science.

Dataset Information

Learning dynamical information from static protein and sequencing data.

Publications

Learning dynamical information from static protein and sequencing data.

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