Pathways and Kinetic Barriers in Mechanical Unfolding and Refolding of RNA and Proteins

Hyeon, Changbong; Dima, Ruxandra I.; Thirumalai, D.

doi:10.1016/j.str.2006.09.002

Cited by 211 publications

(373 citation statements)

References 40 publications

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“…The SOP model, which was introduced to carry out simulations of large systems [52,53], does not include a number of relevant interactions. Most notably, the lack of explicit model for hydrogen bonds, prevents us from examining their role in the allosteric transitions.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Communication in Dihydrofolate Reductase: Signaling Network and Pathways for Closed to Occluded Transition and Back

Chen

Dima

Thirumalai

2007

Journal of Molecular Biology

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113

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1 Abstract E. Coli. dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate.During the catalytic cycle, DHFR undergoes conformational transitions between the closed (CS) and occluded (OS) states which, respectively, describe whether the active site is closed or occluded by the Met20 loop. The CS→OS and the reverse transition may be viewed as allosteric transitions.Using a sequence-based approach we identify a network of residues that represents the allostery wiring

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Section: Discussionmentioning

confidence: 99%

Allosteric Communication in Dihydrofolate Reductase: Signaling Network and Pathways for Closed to Occluded Transition and Back

Chen

Dima

Thirumalai

2007

Journal of Molecular Biology

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113

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“…Self Organised polymer-Side Chain (SOP-SC) Model: We used the SOP-SC (selforganized polymer-side chain) model 41,42 in which each amino acid residue is represented by two beads. One bead is at the C α position representing the backbone atoms, and the other bead is at the center of mass of the side chain representing the side chain atoms.…”

Section: Methodsmentioning

confidence: 99%

“…In this manuscript, we study the burst-phase folding of Protein L to understand the origin of discrepancy between the FRET 21,22 and SAXS 24,25 experiments using the native-centric self-organised polymer model with side chains (SOP-SC) 41,42 and molecular dynamics simulations. The effect of [GuHCl] on Protein L conformations is taken into account using the molecular transfer model (MTM) 11,43 .…”

Section: Introductionmentioning

confidence: 99%

Folding of Protein L with Implications for Collapse in the Denatured State Ensemble

Maity

Reddy

2016

J. Am. Chem. Soc.

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A fundamental question in protein folding is whether the coil to globule collapse transition occurs during the initial stages of folding (burst-phase) or simultaneously with the protein folding transition. Single molecule fluorescence resonance energy transfer (FRET) and small angle X-ray scattering (SAXS) experiments disagree on whether Protein L collapse transition occurs during the burst-phase of folding. We study Protein L folding using a coarse-grained model and molecular dynamics simulations. The collapse transition in Protein L is found to be concomitant with the folding transition. In the burst-phase of folding, we find that FRET experiments overestimate radius of gyration, R g , of the protein due to the application of Gaussian polymer chain end-to-end distribution to extract R g from the FRET efficiency. FRET experiments estimate ≈ 6Å decrease in R g when the actual decrease is ≈ 3Å on Guanidinium Chloride denaturant dilution from 7.5M to 1M, and thereby suggesting pronounced compaction in the protein dimensions in the burst-phase.The ≈ 3Å decrease is close to the statistical uncertainties of the R g data measured from SAXS experiments, which suggest no compaction, leading to a disagreement with the FRET experiments.

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“…To initiate refolding, we reduced the force on the fully stretched GFP to a quench force, f Q = 0. Formation of secondary structures and establishment of a large number of tertiary contacts occurs rapidly, in about 2.5 ms. 111 Subsequently, the molecule pauses in a metastable intermediate state in which all the secondary structural elements are formed but the characteristic barrel of the native state is absent. The transition from the metastable intermediate to the NBA, during which the barrel forms, is the rate limiting step.…”

Section: Gfp Refolding Upon Force Quenchmentioning

confidence: 99%

“…111 In both AFM and LOT experiments, force is applied to one end of the chain (3 end) while the other end is fixed. The initially applied tension propagates over time in a nonuniform fashion through a network of interactions that stabilize the native conformation.…”

Section: Stretching Azoarcus Ribozymementioning

confidence: 99%

Minimal Models for Proteins and RNA: From Folding to Function

Pincus

Cho

Hyeon

et al. 2008

Progress in Molecular Biology and Translational Science

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We present a panoramic view of the utility of coarse-grained (CG) models to study folding and functions of proteins and RNA. Drawing largely on the methods developed in our group over the last twenty years, we describe a number of key applications ranging from folding of proteins with disulfide bonds to functions of molecular machines. After presenting the theoretical basis that justifies the use of CG models, we explore the biophysical basis for the emergence of a finite number of folds from lattice models. The lattice model simulations of approach to the folded state show that non-native interactions are relevant only early in the folding process -a finding that rationalizes the success of structure-based models that emphasize native interactions. Applications of off-lattice C α and models that explicitly consider side chains (C α -SCM) to folding of β-hairpin and effects of macromolecular crowding are briefly discussed. Successful applications of a new class of off-lattice models, referred to as the Self- We also present two distinct models for RNA, namely, the Three Site Interaction (TIS) model and the SOP model, that probe forced unfolding and force quench refolding of a simple hairpin and Azoarcus ribozyme. The unfolding pathways of Azoarcus ribozyme depend on the loading rate, while constant force and constant loading rate simulations of the hairpin show that both forced-unfolding and force-quench refolding pathways are heterogeneous. The location of the transition state moves as force is varied. The predictions based on the SOP model show that force-induced unfolding pathways of the ribozyme can be dramatically changed by varying the loading rate. We conclude with a discussion of future prospects for the use of coarse-grained models in addressing problems of outstanding interest in biology.

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Pathways and Kinetic Barriers in Mechanical Unfolding and Refolding of RNA and Proteins

Cited by 211 publications

References 40 publications

Allosteric Communication in Dihydrofolate Reductase: Signaling Network and Pathways for Closed to Occluded Transition and Back

Allosteric Communication in Dihydrofolate Reductase: Signaling Network and Pathways for Closed to Occluded Transition and Back

Folding of Protein L with Implications for Collapse in the Denatured State Ensemble

Minimal Models for Proteins and RNA: From Folding to Function

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