A simple theoretical model goes a long way in explaining complex behavior in protein folding

Muñoz, Víctor

doi:10.1073/pnas.1418039111

Cited by 8 publications

(4 citation statements)

References 19 publications

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“…We used a coarse-grained SBM to investigate folding of a multidomain protein under different environments mimicking the in vivo conditions. SBM and other methodologies inspired from the energy landscape theory were initially designed for single domain protein folding; , however, the recent successes with applications to multidomain protein folding verify their portability in tackling the more complex folding behaviors. , In addition, the highly consistent folding pictures of DPO4 obtained independently by our simulations and experiments serve as the solid bases for the current work on DPO4 folding with confinements and crowders.…”

Section: Discussionmentioning

confidence: 69%

Confinement and Crowding Effects on Folding of a Multidomain Y-Family DNA Polymerase

Chu

Suo

Wang

2020

J. Chem. Theory Comput.

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Proteins in vivo endure highly various interactions from the luxuriant surrounding macromolecular cosolutes. Confinement and macromolecular crowding are the two major effects that should be considered while comparing the results of protein dynamics from in vitro to in vivo. However, efforts have been largely focused on single domain protein folding up to now, and the quantifications of the in vivo effects in terms of confinements and crowders on modulating the structure and dynamics as well as the physical understanding of the underlying mechanisms on multidomain protein folding are still challenging. Here we developed a topology-based model to investigate folding of a multidomain Y-family DNA polymerase (DPO4) within spherical confined space and in the presence of repulsive and attractive crowders. We uncovered that the entropic component of the thermodynamic driving force led by confinements and repulsive crowders increases the stability of folded states relative to the folding intermediates and unfolded states, while the enthalpic component of the thermodynamic driving force led by attractive crowders gives rise to the opposite effects with less stability. We found that the shapes of DPO4 conformations influenced by the confinements and the crowders are quite different even when only the entropic component of the thermodynamic driving force is considered. We uncovered that under all in vivo conditions, the folding cooperativity of DPO4 decreases compared to that in bulk. We showed that the loss of folding cooperativity can promote the sequential domain-wise folding, which was widely found in cotranslational multidomain protein folding, and effectively prohibit the backtracking led by topological frustrations during multidomain protein folding processes.

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Section: Discussionmentioning

confidence: 69%

Confinement and Crowding Effects on Folding of a Multidomain Y-Family DNA Polymerase

Chu

Suo

Wang

2020

J. Chem. Theory Comput.

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“…The driving force behind folding is the self-organized critical behaviour caused by hydrophobic interactions [32]. There are numerous indications that folding kinetics is defined by the structural topological properties of proteins [33][34][35][36]. Rajasekaran et al [37] studied the distance for which the information on perturbation is transmitted within a molecule.…”

Section: Effect Of Topological Properties On Folding and Molecular In...mentioning

confidence: 99%

Topological bio-scaling analysis as a universal measure of protein folding

2022

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Scaling relationships for polymeric molecules establish power law dependencies between the number of molecular segments and linear dimensions, such as the radius of gyration. They also establish spatial topological properties of the chains, such as their dimensionality. In the spatial domain, power exponents α = 1 (linear stretched molecule), α = 0.5 (the ideal chain) and α = 0.333 (compact globule) are significant. During folding, the molecule undergoes the transition from the one-dimensional linear to the three-dimensional globular state within a very short time. However, intermediate states with fractional dimensions can be stabilized by modifying the solubility (e.g. by changing the solution temperature). Topological properties, such as dimension, correlate with the interaction energy, and thus by tuning the solubility one can control molecular interaction. We investigate these correlations using the example of a well-studied short model of Trp-cage protein. The radius of gyration is used to estimate the fractal dimension of the chain at different stages of folding. It is expected that the same principle is applicable to much larger molecules and that topological (dimensional) characteristics can provide insights into molecular folding and interactions.

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“…In this model, even when the inserted continuous domain (ABD) is not folded, non-local interactions can be formed between the N- and C-terminal regions involved in DLD via the virtual linker. The free-energy landscape calculated by the eWSME model successfully predicts the two of the six folding intermediates reported in the experiments [ 45 , 132 ]. Furthermore, Sasai et al proposed that the introduction of multiple virtual linkers into a protein molecule may enable the prediction of the folding processes of multi-domain proteins with more than two domains [ 17 ].…”

Section: Folding Mechanisms Of Multi-domain Proteinsmentioning

confidence: 96%

The Wako-Saitô-Muñoz-Eaton Model for Predicting Protein Folding and Dynamics

2022

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Despite the recent advances in the prediction of protein structures by deep neutral networks, the elucidation of protein-folding mechanisms remains challenging. A promising theory for describing protein folding is a coarse-grained statistical mechanical model called the Wako–Saitô–Muñoz–Eaton (WSME) model. The model can calculate the free-energy landscapes of proteins based on a three-dimensional structure with low computational complexity, thereby providing a comprehensive understanding of the folding pathways and the structure and stability of the intermediates and transition states involved in the folding reaction. In this review, we summarize previous and recent studies on protein folding and dynamics performed using the WSME model and discuss future challenges and prospects. The WSME model successfully predicted the folding mechanisms of small single-domain proteins and the effects of amino-acid substitutions on protein stability and folding in a manner that was consistent with experimental results. Furthermore, extended versions of the WSME model were applied to predict the folding mechanisms of multi-domain proteins and the conformational changes associated with protein function. Thus, the WSME model may contribute significantly to solving the protein-folding problem and is expected to be useful for predicting protein folding, stability, and dynamics in basic research and in industrial and medical applications.

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A simple theoretical model goes a long way in explaining complex behavior in protein folding

Cited by 8 publications

References 19 publications

Confinement and Crowding Effects on Folding of a Multidomain Y-Family DNA Polymerase

Confinement and Crowding Effects on Folding of a Multidomain Y-Family DNA Polymerase

Topological bio-scaling analysis as a universal measure of protein folding

The Wako-Saitô-Muñoz-Eaton Model for Predicting Protein Folding and Dynamics

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