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A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy.

ABSTRACT: For small molecule reaction kinetics, computed reaction coordinates often mimic experimentally measured observables quite accurately. Although nowadays simulated and measured biomolecule kinetics can be compared on the same time scale, a gap between computed and experimental observables remains. Here we directly compared temperature-jump experiments and molecular dynamics simulations of protein folding dynamics using the same observable: the time-dependent infrared spectrum. We first measured the stability and folding kinetics of the fastest-folding ?-protein, the GTT35 WW domain, using its structurally specific infrared spectrum. The relaxation dynamics of the peptide backbone, ?-sheets, turn, and random coil were measured independently by probing the amide I' region at different frequencies. Next, the amide I' spectra along folding/unfolding molecular dynamics trajectories were simulated by accurate mixed quantum/classical calculations. The simulated time dependence and spectral amplitudes at the exact experimental probe frequencies provided relaxation and folding rates in agreement with experimental observations. The calculations validated by experiment yield direct structural evidence for a rate-limiting reaction step where an intermediate state with either the first or second hairpin is formed. We show how folding switches from a more homogeneous (apparent two-state) process at high temperature to a more heterogeneous process at low temperature, where different parts of the WW domain fold at different rates.

SUBMITTER: Davis CM

PROVIDER: S-EPMC6301204 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy.

Davis Caitlin M CM Zanetti-Polzi Laura L Gruebele Martin M Amadei Andrea A Dyer R Brian RB Daidone Isabella I

Chemical science 20181003 48

For small molecule reaction kinetics, computed reaction coordinates often mimic experimentally measured observables quite accurately. Although nowadays simulated and measured biomolecule kinetics can be compared on the same time scale, a gap between computed and experimental observables remains. Here we directly compared temperature-jump experiments and molecular dynamics simulations of protein folding dynamics using the same observable: the time-dependent infrared spectrum. We first measured th ...[more]

PMID: 30647892

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Project description:Vibrational spectroscopy is an essential tool in chemical analyses, biological assays, and studies of functional materials. Over the past decade, various coherent nonlinear vibrational spectroscopic techniques have been developed and enabled researchers to study time-correlations of the fluctuating frequencies that are directly related to solute-solvent dynamics, dynamical changes in molecular conformations and local electrostatic environments, chemical and biochemical reactions, protein structural dynamics and functions, characteristic processes of functional materials, and so on. In order to gain incisive and quantitative information on the local electrostatic environment, molecular conformation, protein structure and interprotein contacts, ligand binding kinetics, and electric and optical properties of functional materials, a variety of vibrational probes have been developed and site-specifically incorporated into molecular, biological, and material systems for time-resolved vibrational spectroscopic investigation. However, still, an all-encompassing theory that describes the vibrational solvatochromism, electrochromism, and dynamic fluctuation of vibrational frequencies has not been completely established mainly due to the intrinsic complexity of intermolecular interactions in condensed phases. In particular, the amount of data obtained from the linear and nonlinear vibrational spectroscopic experiments has been rapidly increasing, but the lack of a quantitative method to interpret these measurements has been one major obstacle in broadening the applications of these methods. Among various theoretical models, one of the most successful approaches is a semiempirical model generally referred to as the vibrational spectroscopic map that is based on a rigorous theory of intermolecular interactions. Recently, genetic algorithm, neural network, and machine learning approaches have been applied to the development of vibrational solvatochromism theory. In this review, we provide comprehensive descriptions of the theoretical foundation and various examples showing its extraordinary successes in the interpretations of experimental observations. In addition, a brief introduction to a newly created repository Web site (http://frequencymap.org) for vibrational spectroscopic maps is presented. We anticipate that a combination of the vibrational frequency map approach and state-of-the-art multidimensional vibrational spectroscopy will be one of the most fruitful ways to study the structure and dynamics of chemical, biological, and functional molecular systems in the future.

Project description:MotivationThe function of an RNA molecule is not only linked to its native structure, which is usually taken to be the ground state of its folding landscape, but also in many cases crucially depends on the details of the folding pathways such as stable folding intermediates or the timing of the folding process itself. To model and understand these processes, it is necessary to go beyond ground state structures. The study of rugged RNA folding landscapes holds the key to answer these questions. Efficient coarse-graining methods are required to reduce the intractably vast energy landscapes into condensed representations such as barrier trees or basin hopping graphs : BHG) that convey an approximate but comprehensive picture of the folding kinetics. So far, exact and heuristic coarse-graining methods have been mostly restricted to the pseudoknot-free secondary structures. Pseudoknots, which are common motifs and have been repeatedly hypothesized to play an important role in guiding folding trajectories, were usually excluded.ResultsWe generalize the BHG framework to include pseudoknotted RNA structures and systematically study the differences in predicted folding behavior depending on whether pseudoknotted structures are allowed to occur as folding intermediates or not. We observe that RNAs with pseudoknotted ground state structures tend to have more pseudoknotted folding intermediates than RNAs with pseudoknot-free ground state structures. The occurrence and influence of pseudoknotted intermediates on the folding pathway, however, appear to depend very strongly on the individual RNAs so that no general rule can be inferred.Availability and implementationThe algorithms described here are implemented in C++ as standalone programs. Its source code and Supplemental material can be freely downloaded from http://www.tbi.univie.ac.at/bhg.html.Contactqin@bioinf.uni-leipzig.deSupplementary informationSupplementary data are available at Bioinformatics online.

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A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy.

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A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy.

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