Reply to Alberti: Are in vitro folding experiments relevant in vivo?

Zhuravlev, Pavel I.; Hinczewski, Michael; Chakrabarti, Shaon; Marqusee, Susan; Thirumalai, D.

doi:10.1073/pnas.1603395113

Cited by 6 publications

(6 citation statements)

References 10 publications

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“…We argued that because SH3 has only one dominant pathway, HI has less of an effect on the folding rate as that of CI2 at T< f T . Additionally, several single molecule pulling experiments have also shown that the addition of more than one order parameter is necessary to describe folding [56,57]. Even though Woodside and coworkers have shown that it is possible to use a single reaction coordinate to characterize the entire folding landscape for a specific protein, they are not able to claim that it is possible for all proteins, however [58].…”

Section: B Underlying Kinetic Principles Of the Crossover Behaviormentioning

confidence: 99%

Impact of hydrodynamic interactions on protein folding rates depends on temperature

et al. 2018

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We investigated the impact of hydrodynamic interactions (HI) on protein folding using a coarse-grained model. The extent of the impact of hydrodynamic interactions, whether it accelerates, retards, or has no effect on protein folding, has been controversial. Together with a theoretical framework of the energy landscape theory (ELT) for protein folding that describes the dynamics of the collective motion with a single reaction coordinate across a folding barrier, we compared the kinetic effects of HI on the folding rates of two protein models that use a chain of single beads with distinctive topologies: a 64-residue α/β chymotrypsin inhibitor 2 (CI2) protein, and a 57-residue β-barrel α-spectrin Src-homology 3 domain (SH3) protein. When comparing the protein folding kinetics simulated with Brownian dynamics in the presence of HI to that in the absence of HI, we find that the effect of HI on protein folding appears to have a “crossover” behavior about the folding temperature. This means that at a temperature greater than the folding temperature, the enhanced friction from the hydrodynamic solvents between the beads in an unfolded configuration results in lowered folding rate; conversely, at a temperature lower than the folding temperature, HI accelerates folding by the backflow of solvent toward the folded configuration of a protein. Additionally, the extent of acceleration depends on the topology of a protein: for a protein like CI2, where its folding nucleus is rather diffuse in a transition state, HI channels the formation of contacts by favoring a major folding pathway in a complex free energy landscape, thus accelerating folding. For a protein like SH3, where its folding nucleus is already specific and less diffuse, HI matters less at a temperature lower than the folding temperature. Our findings provide further theoretical insight to protein folding kinetic experiments and simulations.

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Section: B Underlying Kinetic Principles Of the Crossover Behaviormentioning

confidence: 99%

Impact of hydrodynamic interactions on protein folding rates depends on temperature

et al. 2018

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“…The most obvious achievement lies in its broad applicability and it is now possible to directly compare the results of experiments recorded at vastly different pulling speeds. A very important issue is concerned with the possible speed-dependent change in the pathway of mechanical unfolding, in particular the crossover from thermal to mechanical unfolding [29,49]. Also the impact of dynamic disorder in the mechanical unfolding can be investigated over a huge range of rates and thus might allow to probe different regimes of this fascinating topic [50].…”

Section: Discussionmentioning

confidence: 99%

Dynamic coarse-graining fills the gap between atomistic simulations and experimental investigations of mechanical unfolding

Knoch

Schafer

Diezemann

et al. 2018

The Journal of Chemical Physics

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We present a dynamic coarse-graining technique that allows one to simulate the mechanical unfolding of biomolecules or molecular complexes on experimentally relevant time scales. It is based on Markov state models (MSMs), which we construct from molecular dynamics simulations using the pulling coordinate as an order parameter. We obtain a sequence of MSMs as a function of the discretized pulling coordinate, and the pulling process is modeled by switching among the MSMs according to the protocol applied to unfold the complex. This way we cover seven orders of magnitude in pulling speed. In the region of rapid pulling, we additionally perform steered molecular dynamics simulations and find excellent agreement between the results of the fully atomistic and the dynamically coarse-grained simulations. Our technique allows the determination of the rates of mechanical unfolding in a dynamical range from approximately 10/ns to 1/ns thus reaching experimentally accessible time regimes without abandoning atomistic resolution.

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“…26 Recently, simulated AFM was applied to investigate unfolding of the cold shock protein B (Csp) 27 and the Src SH3 domain. 28 SMD has also been used to probe mechanical resistance of peptide-receptor interactions. 29 In this study, we hypothesized that, under MD-simulated stress, models with a high structural similarity to their native conformation would be more resistant to unfolding than models with more inaccurate folds.…”

Section: Introductionmentioning

confidence: 99%

“…Early applications of SMD used to mimic AFM on biological systems were performed by the Schulten group to study the unbinding of the avidin‐biotin complex 24 and the unfolding pathway of titin IG domains, 25 which showed good agreement with contemporary experiments using AFM 26 . Recently, simulated AFM was applied to investigate unfolding of the cold shock protein B (Csp) 27 and the Src SH3 domain 28 . SMD has also been used to probe mechanical resistance of peptide‐receptor interactions 29 …”

Section: Introductionmentioning

confidence: 99%

Using steered molecular dynamic tension for assessing quality of computational protein structure models

Monroe

2022

J Comput Chem

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The native structures of proteins, except for notable exceptions of intrinsically disordered proteins, in general take their most stable conformation in the physiological condition to maintain their structural framework so that their biological function can be properly carried out. Experimentally, the stability of a protein can be measured by several means, among which the pulling experiment using the atomic force microscope (AFM) stands as a unique method. AFM directly measures the resistance from unfolding, which can be quantified from the observed force‐extension profile. It has been shown that key features observed in an AFM pulling experiment can be well reproduced by computational molecular dynamics simulations. Here, we applied computational pulling for estimating the accuracy of computational protein structure models under the hypothesis that the structural stability would positively correlated with the accuracy, i.e. the closeness to the native, of a model. We used in total 4929 structure models for 24 target proteins from the Critical Assessment of Techniques of Structure Prediction (CASP) and investigated if the magnitude of the break force, that is, the force required to rearrange the model's structure, from the force profile was sufficient information for selecting near‐native models. We found that near‐native models can be successfully selected by examining their break forces suggesting that high break force indeed indicates high stability of models. On the other hand, there were also near‐native models that had relatively low peak forces. The mechanisms of the stability exhibited by the break forces were explored and discussed.

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Reply to Alberti: Are in vitro folding experiments relevant in vivo?

Cited by 6 publications

References 10 publications

Impact of hydrodynamic interactions on protein folding rates depends on temperature

Impact of hydrodynamic interactions on protein folding rates depends on temperature

Dynamic coarse-graining fills the gap between atomistic simulations and experimental investigations of mechanical unfolding

Using steered molecular dynamic tension for assessing quality of computational protein structure models

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