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Vijay S Pande - One of the best experts on this subject based on the ideXlab platform.

  • Emergence of glass-like behavior in Markov state models of protein Folding Dynamics.
    Journal of the American Chemical Society, 2013
    Co-Authors: Jeffrey K. Weber, Robert L. Jack, Vijay S Pande
    Abstract:

    The extent to which glass-like kinetics govern Dynamics in protein Folding has been heavily debated. Here, we address the subject with an application of space-time perturbation theory to the Dynamics of protein Folding Markov state models. Borrowing techniques from the s-ensemble method, we argue that distinct active and inactive phases exist for protein Folding Dynamics, and that kinetics for specific systems can fall into either dynamical regime. We do not, however, observe a true glass transition in any system studied. We go on to discuss how these inactive and active phases might relate to general protein Folding properties.

  • solvent viscosity dependence of the protein Folding Dynamics
    Journal of Physical Chemistry B, 2008
    Co-Authors: Young Min Rhee, Vijay S Pande
    Abstract:

    Solvent viscosity has been frequently adopted as an adjustable parameter in various computational studies (e.g., protein Folding simulations) with implicit solvent models. A common approach is to use low viscosities to expedite simulations. While using viscosities lower than that of aqueous is unphysical, such treatment is based on observations that the viscosity affects the kinetics (rates) in a well-defined manner as described by Kramers' theory. Here, we investigate the effect of viscosity on the detailed Dynamics (mechanism) of protein Folding. On the basis of a simple mathematical model, we first show that viscosity may indeed affect the Dynamics in a complex way. By applying the model to the Folding of a small protein, we demonstrate that the detailed Dynamics is affected rather pronouncedly especially at unphysically low viscosities, cautioning against using such viscosities. In this regard, our model may also serve as a diagnostic tool for validating low-viscosity simulations. It is also suggested...

  • Solvent viscosity dependence of the protein Folding Dynamics.
    The Journal of Physical Chemistry B, 2008
    Co-Authors: Young Min Rhee, Vijay S Pande
    Abstract:

    Solvent viscosity has been frequently adopted as an adjustable parameter in various computational studies (e.g., protein Folding simulations) with implicit solvent models. A common approach is to use low viscosities to expedite simulations. While using viscosities lower than that of aqueous is unphysical, such treatment is based on observations that the viscosity affects the kinetics (rates) in a well-defined manner as described by Kramers' theory. Here, we investigate the effect of viscosity on the detailed Dynamics (mechanism) of protein Folding. On the basis of a simple mathematical model, we first show that viscosity may indeed affect the Dynamics in a complex way. By applying the model to the Folding of a small protein, we demonstrate that the detailed Dynamics is affected rather pronouncedly especially at unphysically low viscosities, cautioning against using such viscosities. In this regard, our model may also serve as a diagnostic tool for validating low-viscosity simulations. It is also suggested that the viscosity dependence can be further exploited to gain information about the protein Folding mechanism.

  • Does Native State Topology Determine the RNA Folding Mechanism
    Journal of Molecular Biology, 2004
    Co-Authors: Eric J. Sorin, Bradley J. Nakatani, Guha Jayachandran, Young Min Rhee, Vikram Vishal, Vijay S Pande
    Abstract:

    Recent studies in protein Folding suggest that native state topology plays a dominant role in determining the Folding mechanism, yet an analogous statement has not been made for RNA, most likely due to the strong coupling between the ionic environment and conformational energetics that make RNA Folding more complex than protein Folding. Applying a distributed computing architecture to sample nearly 5000 complete tRNA Folding events using a minimalist, atomistic model, we have characterized the role of native topology in tRNA Folding Dynamics: the simulated bulk Folding behavior predicts well the experimentally observed Folding mechanism. In contrast, single-molecule Folding events display multiple discrete Folding transitions and compose a largely diverse, heterogeneous dynamic ensemble. This both supports an emerging view of heterogeneous Folding Dynamics at the microscopic level and highlights the need for single-molecule experiments and both single-molecule and bulk simulations in interpreting bulk experimental measurements.

  • absolute comparison of simulated and experimental protein Folding Dynamics
    Nature, 2002
    Co-Authors: Christopher D Snow, Vijay S Pande, Houbi Nguyen, Martin Gruebele
    Abstract:

    Protein Folding is difficult to simulate with classical molecular Dynamics. Secondary structure motifs such as α-helices and β-hairpins can form in 0.1–10 µs (ref. 1), whereas small proteins have been shown to fold completely in tens of microseconds2. The longest Folding simulation to date is a single 1-µs simulation of the villin headpiece3; however, such single runs may miss many features of the Folding process as it is a heterogeneous reaction involving an ensemble of transition states4,5. Here, we have used a distributed computing implementation to produce tens of thousands of 5–20-ns trajectories (700 µs) to simulate mutants of the designed mini-protein BBA5. The fast relaxation Dynamics these predict were compared with the results of laser temperature-jump experiments. Our computational predictions are in excellent agreement with the experimentally determined mean Folding times and equilibrium constants. The rapid Folding of BBA5 is due to the swift formation of secondary structure. The convergence of experimentally and computationally accessible timescales will allow the comparison of absolute quantities characterizing in vitro and in silico (computed) protein Folding6.

Stephen J Hagen - One of the best experts on this subject based on the ideXlab platform.

  • Folding Dynamics and pathways of the trp-cage miniproteins.
    Biochemistry, 2014
    Co-Authors: Aimee Byrne, Brandon L Kier, Stephen J Hagen, D. Victoria Williams, Bipasha Barua, Niels H. Andersen
    Abstract:

    Using alternate measures of fold stability for a wide variety of Trp-cage mutants has raised the possibility that prior Dynamics T-jump measures may not be reporting on complete cage formation for some species. NMR relaxation studies using probes that only achieve large chemical shift difference from unfolded values on complete cage formation indicate slower Folding in some but not all cases. Fourteen species have been examined, with cage formation time constants (1/kF) ranging from 0.9–7.5 μs at 300 K. The present study does not change the status of the Trp-cage as a fast Folding, essentially two-state system, although it does alter the stage at which this description applies. A diversity of prestructuring events, depending on the specific analogue examined, may appear in the Folding scenario, but in all cases, formation of the N-terminal helix is complete either at or before the cage-formation transition state. In contrast, the fold-stabilizing H-bonding interactions of the buried Ser14 side chain and t...

  • solvent viscosity and friction in protein Folding Dynamics
    Current Protein & Peptide Science, 2010
    Co-Authors: Stephen J Hagen
    Abstract:

    The famous Kramers rate theory for diffusion-controlled reactions has been extended in numerous ways and successfully applied to many types of reactions. Its application to protein Folding reactions has been of particular interest in recent years, as many researchers have performed experiments and simulations to test whether Folding reactions are diffusion-controlled, whether the solvent is the source of the reaction friction, and whether the friction-dependence of Folding rates generally can provide insight into Folding Dynamics. These experiments involve many practical difficulties, however. They have also produced some unexpected results. Here we briefly review the Kramers theory for reactions in the presence of strong friction and summarize some of the subtle problems that arise in the application of the theory to protein Folding. We discuss how the results of these experiments ultimately point to a significant role for internal friction in protein Folding Dynamics. Studies of friction in protein Folding, far from revealing any weakness in Kramers theory, may actually lead to new approaches for probing diffusional Dynamics and energy landscapes in protein Folding.

  • a limiting speed for protein Folding at low solvent viscosity
    Journal of the American Chemical Society, 2004
    Co-Authors: Stephen J Hagen
    Abstract:

    Because protein Folding Dynamics are heavily overdamped, Kramers theory predicts the rate of Folding to scale inversely with the reaction friction, which is usually interpreted to mean the solvent viscosity. This does not mean, however, that the speed of Folding can increase without limit as solvent viscosity decreases. We show that, in a sufficiently fast-Folding protein, the Folding speed approaches a finite limit at low solvent viscosity, indicating a reaction controlled by internal friction.

Young Min Rhee - One of the best experts on this subject based on the ideXlab platform.

  • solvent viscosity dependence of the protein Folding Dynamics
    Journal of Physical Chemistry B, 2008
    Co-Authors: Young Min Rhee, Vijay S Pande
    Abstract:

    Solvent viscosity has been frequently adopted as an adjustable parameter in various computational studies (e.g., protein Folding simulations) with implicit solvent models. A common approach is to use low viscosities to expedite simulations. While using viscosities lower than that of aqueous is unphysical, such treatment is based on observations that the viscosity affects the kinetics (rates) in a well-defined manner as described by Kramers' theory. Here, we investigate the effect of viscosity on the detailed Dynamics (mechanism) of protein Folding. On the basis of a simple mathematical model, we first show that viscosity may indeed affect the Dynamics in a complex way. By applying the model to the Folding of a small protein, we demonstrate that the detailed Dynamics is affected rather pronouncedly especially at unphysically low viscosities, cautioning against using such viscosities. In this regard, our model may also serve as a diagnostic tool for validating low-viscosity simulations. It is also suggested...

  • Solvent viscosity dependence of the protein Folding Dynamics.
    The Journal of Physical Chemistry B, 2008
    Co-Authors: Young Min Rhee, Vijay S Pande
    Abstract:

    Solvent viscosity has been frequently adopted as an adjustable parameter in various computational studies (e.g., protein Folding simulations) with implicit solvent models. A common approach is to use low viscosities to expedite simulations. While using viscosities lower than that of aqueous is unphysical, such treatment is based on observations that the viscosity affects the kinetics (rates) in a well-defined manner as described by Kramers' theory. Here, we investigate the effect of viscosity on the detailed Dynamics (mechanism) of protein Folding. On the basis of a simple mathematical model, we first show that viscosity may indeed affect the Dynamics in a complex way. By applying the model to the Folding of a small protein, we demonstrate that the detailed Dynamics is affected rather pronouncedly especially at unphysically low viscosities, cautioning against using such viscosities. In this regard, our model may also serve as a diagnostic tool for validating low-viscosity simulations. It is also suggested that the viscosity dependence can be further exploited to gain information about the protein Folding mechanism.

  • Does Native State Topology Determine the RNA Folding Mechanism
    Journal of Molecular Biology, 2004
    Co-Authors: Eric J. Sorin, Bradley J. Nakatani, Guha Jayachandran, Young Min Rhee, Vikram Vishal, Vijay S Pande
    Abstract:

    Recent studies in protein Folding suggest that native state topology plays a dominant role in determining the Folding mechanism, yet an analogous statement has not been made for RNA, most likely due to the strong coupling between the ionic environment and conformational energetics that make RNA Folding more complex than protein Folding. Applying a distributed computing architecture to sample nearly 5000 complete tRNA Folding events using a minimalist, atomistic model, we have characterized the role of native topology in tRNA Folding Dynamics: the simulated bulk Folding behavior predicts well the experimentally observed Folding mechanism. In contrast, single-molecule Folding events display multiple discrete Folding transitions and compose a largely diverse, heterogeneous dynamic ensemble. This both supports an emerging view of heterogeneous Folding Dynamics at the microscopic level and highlights the need for single-molecule experiments and both single-molecule and bulk simulations in interpreting bulk experimental measurements.

Niels H. Andersen - One of the best experts on this subject based on the ideXlab platform.

  • Folding Dynamics and pathways of the trp-cage miniproteins.
    Biochemistry, 2014
    Co-Authors: Aimee Byrne, Brandon L Kier, Stephen J Hagen, D. Victoria Williams, Bipasha Barua, Niels H. Andersen
    Abstract:

    Using alternate measures of fold stability for a wide variety of Trp-cage mutants has raised the possibility that prior Dynamics T-jump measures may not be reporting on complete cage formation for some species. NMR relaxation studies using probes that only achieve large chemical shift difference from unfolded values on complete cage formation indicate slower Folding in some but not all cases. Fourteen species have been examined, with cage formation time constants (1/kF) ranging from 0.9–7.5 μs at 300 K. The present study does not change the status of the Trp-cage as a fast Folding, essentially two-state system, although it does alter the stage at which this description applies. A diversity of prestructuring events, depending on the specific analogue examined, may appear in the Folding scenario, but in all cases, formation of the N-terminal helix is complete either at or before the cage-formation transition state. In contrast, the fold-stabilizing H-bonding interactions of the buried Ser14 side chain and t...

  • circular permutation of a ww domain Folding still occurs after excising the turn of the Folding nucleating hairpin
    Journal of the American Chemical Society, 2014
    Co-Authors: Brandon L Kier, Jordan M Anderson, Niels H. Andersen
    Abstract:

    A hyperstable Pin1 WW domain has been circularly permuted via excision of the fold-nucleating turn; it still folds to form the native three-strand sheet and hydrophobic core features. Multiprobe Folding Dynamics studies of the normal and circularly permuted sequences, as well as their constituent hairpin fragments and comparable-length β-strand-loop-β-strand models, indicate 2-state Folding for all topologies. N-terminal hairpin formation is the fold nucleating event for the wild-type sequence; the slower Folding circular permutant has a more distributed Folding transition state.

  • Mutational effects on the Folding Dynamics of a minimized hairpin.
    Biochemistry, 2013
    Co-Authors: Michele Scian, Irene Shu, Katherine A. Olsen, Khalil Hassam, Niels H. Andersen
    Abstract:

    The fold stabilities and Folding Dynamics of a series of mutants of a model hairpin, KTW-NPATGK-WTE (HP7), are reported. The parent system and the corresponding DPATGK loop species display submicrosecond Folding time constants. The mutational studies revealed that ultrafast Folding requires both some prestructuring of the loop and a favorable interaction between the chain termini in the transition state. In the case of YY-DPETGT-WY, another submicrosecond Folding species [Davis, C. M., Xiao, S., Raleigh, D. P., and Dyer, R. B. (2012) J. Am. Chem. Soc. 134, 14476–14482], a hydrophobic cluster provides the latter. In the case of HP7, the Coulombic interaction between the terminal NH3+ and CO2– units provides this; a C-terminal Glu to amidated Ala mutation results in a 5-fold retardation of the Folding rate. The effects of mutations within the reversing loop indicate the balance between loop flexibility (favoring fast conformational searching) and turn formation in the unfolded state is a major factor in det...

Jungkweon Choi - One of the best experts on this subject based on the ideXlab platform.

  • Folding Dynamics of cytochrome c using pulse radiolysis.
    Journal of the American Chemical Society, 2012
    Co-Authors: Jungkweon Choi, Mamoru Fujitsuka, Sachiko Tojo, Tetsuro Majima
    Abstract:

    Pulse radiolysis is a powerful method to realize real-time observation of various redox processes, which induces various structural and functional changes occurring in biological systems. However, its application has been mainly limited to studies of the redox reactions of rather smaller biological systems such as DNA because of an undesired reaction due to various free radicals generated by pulse radiolysis. For application of pulse radiolysis to generate plenty of redox reactions of biological systems, selective redox reactions induced by electron pulses have to be developed. In this study, we report that in the presence of the high concentration of the denaturant, guanidine HCl (GdHCl), the selective reduction of the oxidized cytochrome c (Cyt c) takes place in time scales of a few microseconds by the electron transfer from the guanidine radical that is formed by the fast reaction of eaq– with GdHCl, consequently leading to Folding kinetics of Cyt c. By providing insight into the Folding Dynamics of Cy...

  • ph induced intramolecular Folding Dynamics of i motif dna
    Journal of the American Chemical Society, 2011
    Co-Authors: Jungkweon Choi, Mamoru Fujitsuka, Sooyeon Kim, Takashi Tachikawa, Tetsuro Majima
    Abstract:

    Using the combination of fluorescence resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS) technique, we investigate the mechanism and Dynamics of the pH-induced conformational change of i-motif DNA in the bulk phases and at the single-molecule level. Despite numerous studies on i-motif that is formed from cytosine (C)-rich strand at slightly acidic pH, its detailed conformational Dynamics have been rarely reported. Using the FRET technique to provide valuable information on the structure of biomolecules such as a protein and DNA, we clearly show that the partially folded species as well as the single-stranded structure coexist at neutral pH, supporting that the partially folded species may exist substantially in vivo and play an important role in a process of gene expression. By measuring the FCS curves of i-motif, we observed the gradual decrease of the diffusion coefficient of i-motif with increasing pH. The quantitative analysis of FCS curves supports that the gradual decre...

  • Protein Folding Dynamics of cytochrome c seen by transient grating and transient absorption spectroscopies.
    The Journal of Physical Chemistry B, 2011
    Co-Authors: Jungkweon Choi, Cheolhee Yang, Jeongho Kim, Hyotcherl Ihee
    Abstract:

    We investigate optically triggered protein Folding Dynamics of cytochrome c (Cytc) using transient grating (TG) and transient absorption (TA) spectroscopies. Despite many studies on protein Folding Dynamics of Cytc, a well-known model protein, direct spectroscopic evidence for the three-dimensional global Folding process has been rarely reported. By measuring the TG signal of CO-bound Cytc (Cytc-CO) in the presence of a denaturant, we clearly detected the change of diffusion coefficient that reflects the size change of Cytc upon photodissociation of the CO ligand from unfolded Cytc-CO. The quantitative analysis of TG signals supports that the optically triggered Folding reaction of Cytc in the presence of a denaturant takes place through a detectable intermediate (three-state Folding kinetics). This is in contrast with the two-state Folding Dynamics of Cytc under a denaturant-free environment without any detectable intermediate. (1) From the quantitative global analysis of the TG signals, the rate constants for the U → I and I → N transitions in a CAPS buffer solution (pH 7) at room temperature in the presence of a denaturant at various concentrations are determined to be 1065 ± 17 to 3476 ± 103 s(-1) and 101 ± 6 to 589 ± 21 s(-1), respectively. In addition, the activation energies (E(a)) for the U → I and I → N transitions are determined to be 8.7 ± 1.0 kcal/mol and 7.1 ± 1.3 kcal/mol, respectively. The Folding Dynamics of Cytc initiated by the CO photolysis is discussed based in terms of the protein size change.

  • Folding Dynamics of ferrocytochrome C in a denaturant-free environment probed by transient grating spectroscopy.
    ChemPhysChem, 2008
    Co-Authors: Jungkweon Choi, Cheolhee Yang, Yang Ouk Jung, Jae Hyuk Lee, Bongsoo Kim, Hyotcherl Ihee
    Abstract:

    There have been numerous experimental and theoretical studies that aim to clarify the Folding process occurring in biological systems, but many unsolved important questions still remain for protein Folding. Generally, the Folding processes of most proteins have been interpreted by two-state or sequential mechanisms. The two-state mechanism involves a transition from the unfolded state to the folded state without any detectable intermediates, whereas the sequential mechanism comprises multistate transitions through intermediates. To illuminate the detailed mechanism of protein Folding processes, it is important to detect and characterize the species and intermediates involved in the Folding process. Folding intermediates are short-lived, often heterogeneous, and cannot be studied by the usual crystallographic or NMR methods. Therefore, faster spectroscopic methods, such as time-resolved infrared, time-resolved circular dichroism (CD), 6,13, 14] transient absorption, and stopped-flow optical spectroscopic methods, have been utilized. These diverse methods can provide reaction rates, signal the accumulation of intermediates, and give local information on the role of particular amino acids or averaged parameters of the main chain. However, they do not provide global structural information in general. In this respect, the diffusion coefficient (D), which represents molecular migration in the liquid phase, is certainly a useful quantity for monitoring a protein-Folding process because it is a fundamental physical parameter directly linked to the macromolecular size and shape. Indeed, Terazima and co-workers have shown that the change in diffusion coefficient reflects the conformational change of a biomolecule that occurs in the process of various biological reactions, such as protein Folding. They used laser-induced transient grating (TG) spectroscopy to measure the change in D followed by a protein Folding process. The TG technique can detect a spatial concentration modulation of chemical species induced by laser irradiation. From the temporal profile of the TG signal intensity, the D values of the parent molecule and transient species involved in a photoreaction can be determined directly from the decay rate of the signal measured. In summary, TG spectroscopy provides information about global structural change, whereas transient absorption is more sensitive to local structure and CD is informative for secondary structures. In the study reported herein, we investigate the optically triggered Folding Dynamics of CO-bound ferrocytochrome c (CytC-CO) under highly basic conditions (pH 13) by using timeresolved TG spectroscopy. The Folding Dynamics of CytC with a denaturant has been previously studied by using a combination of the electron transfer of nicotinamide adenine dinucleotide (NADH) and TG spectroscopy. Our study differs in that no denaturant is used so that the effect of the denaturant can be estimated, and the photodissociation of CO is a much faster reaction-triggering method than electron transfer of NADH ( ms), thereby greatly improving the time resolution. Indeed, we captured a process of about 700 ns, which cannot be studied by the latter reaction-triggering method. CytC-CO molecules in strongly basic solution are unfolded without a denaturant, such as guanidine hydrochloride (Gd-HCl) and urea. By contrast, CytC in the absence of the CO ligand has a nativelike structure in terms of secondary and tertiary structural content in strongly basic solutions (see Figure 1). There-