Abstract:A simple statistical mechanical model proposed by Wako and Saitô has explained the aspects of protein folding surprisingly well. This model was systematically applied to multiple proteins by Muñoz and Eaton and has since been referred to as the Wako-Saitô-Muñoz-Eaton (WSME) model. The success of the WSME model in explaining the folding of many proteins has verified the hypothesis that the folding is dominated by native interactions, which makes the energy landscape globally biased toward native conformation. U… Show more
“…Consequently, the WSME model guarantees that both the principle of minimal frustration and consistency principle that locally stable structure is consistent with the final folded, globally stable structure (Gō 1983 ; Bryngelson et al 1995 ). Previous studies showed that the WSME model accurately explains the experimentally observed folding mechanism, i.e., the nucleation–condensation mechanism, of small single-domain proteins (Muñoz and Eaton 1999 ; Itoh and Sasai 2006 ; Sasai et al 2016 ). These results suggest that real small proteins behave as ideal foldable proteins and that the consistency principle holds for small proteins.…”
Section: Folding Mechanisms Of Globular Proteinsmentioning
confidence: 85%
“…Development of theoretical methods for predicting a folding energy landscape and native structure using only an amino acid sequence is one of the major goals of theoretical studies of protein folding (Dill et al 2008 ). One of the most promising theoretical models describing protein folding mechanisms is the Wako–Saitô–Muñoz–Eaton (WSME) model (or island model) (Wako and Saitô 1978a , b ; Muñoz and Eaton 1999 ; Sasai et al 2016 ). The WSME model is a coarse-grained, statistical mechanical model of proteins and enables one to draw a free-energy landscape of a protein-folding reaction using information from the native structure.…”
Section: Folding Mechanisms Of Globular Proteinsmentioning
confidence: 99%
“…Moreover, because the forces responsible for folding and binding are common in globular proteins and IDPs, the WSME model is promising for developing a unified theoretical description of the mechanisms of folding and binding of all proteins. Indeed, the allosteric WSME model has been successfully applied to explain conformational selection and induced-fit mechanisms involved in allosteric transitions of proteins coupled with effector binding (Itoh and Sasai 2010 , 2011 ; Sasai et al 2016 ). Although future improvement in computer simulations may enable the reproduction of folding and binding reactions of all proteins, coarse-grained, statistical mechanical models are still required to determine the physics underlying these biological phenomena.…”
Section: Folding Mechanisms Of Globular Proteinsmentioning
Extensive experimental and theoretical studies have advanced our understanding of the mechanisms of folding and binding of globular proteins, and coupled folding and binding of intrinsically disordered proteins (IDPs). The forces responsible for conformational changes and binding are common in both proteins; however, these mechanisms have been separately discussed. Here, we attempt to integrate the mechanisms of coupled folding and binding of IDPs, folding of small and multi-subdomain proteins, folding of multimeric proteins, and ligand binding of globular proteins in terms of conformational selection and induced-fit mechanisms as well as the nucleation–condensation mechanism that is intermediate between them. Accumulating evidence has shown that both the rate of conformational change and apparent rate of binding between interacting elements can determine reaction mechanisms. Coupled folding and binding of IDPs occurs mainly by induced-fit because of the slow folding in the free form, while ligand binding of globular proteins occurs mainly by conformational selection because of rapid conformational change. Protein folding can be regarded as the binding of intramolecular segments accompanied by secondary structure formation. Multi-subdomain proteins fold mainly by the induced-fit (hydrophobic collapse) mechanism, as the connection of interacting segments enhances the binding (compaction) rate. Fewer hydrophobic residues in small proteins reduce the intramolecular binding rate, resulting in the nucleation–condensation mechanism. Thus, the folding and binding of globular proteins and IDPs obey the same general principle, suggesting that the coarse-grained, statistical mechanical model of protein folding is promising for a unified theoretical description of all mechanisms.
“…Consequently, the WSME model guarantees that both the principle of minimal frustration and consistency principle that locally stable structure is consistent with the final folded, globally stable structure (Gō 1983 ; Bryngelson et al 1995 ). Previous studies showed that the WSME model accurately explains the experimentally observed folding mechanism, i.e., the nucleation–condensation mechanism, of small single-domain proteins (Muñoz and Eaton 1999 ; Itoh and Sasai 2006 ; Sasai et al 2016 ). These results suggest that real small proteins behave as ideal foldable proteins and that the consistency principle holds for small proteins.…”
Section: Folding Mechanisms Of Globular Proteinsmentioning
confidence: 85%
“…Development of theoretical methods for predicting a folding energy landscape and native structure using only an amino acid sequence is one of the major goals of theoretical studies of protein folding (Dill et al 2008 ). One of the most promising theoretical models describing protein folding mechanisms is the Wako–Saitô–Muñoz–Eaton (WSME) model (or island model) (Wako and Saitô 1978a , b ; Muñoz and Eaton 1999 ; Sasai et al 2016 ). The WSME model is a coarse-grained, statistical mechanical model of proteins and enables one to draw a free-energy landscape of a protein-folding reaction using information from the native structure.…”
Section: Folding Mechanisms Of Globular Proteinsmentioning
confidence: 99%
“…Moreover, because the forces responsible for folding and binding are common in globular proteins and IDPs, the WSME model is promising for developing a unified theoretical description of the mechanisms of folding and binding of all proteins. Indeed, the allosteric WSME model has been successfully applied to explain conformational selection and induced-fit mechanisms involved in allosteric transitions of proteins coupled with effector binding (Itoh and Sasai 2010 , 2011 ; Sasai et al 2016 ). Although future improvement in computer simulations may enable the reproduction of folding and binding reactions of all proteins, coarse-grained, statistical mechanical models are still required to determine the physics underlying these biological phenomena.…”
Section: Folding Mechanisms Of Globular Proteinsmentioning
Extensive experimental and theoretical studies have advanced our understanding of the mechanisms of folding and binding of globular proteins, and coupled folding and binding of intrinsically disordered proteins (IDPs). The forces responsible for conformational changes and binding are common in both proteins; however, these mechanisms have been separately discussed. Here, we attempt to integrate the mechanisms of coupled folding and binding of IDPs, folding of small and multi-subdomain proteins, folding of multimeric proteins, and ligand binding of globular proteins in terms of conformational selection and induced-fit mechanisms as well as the nucleation–condensation mechanism that is intermediate between them. Accumulating evidence has shown that both the rate of conformational change and apparent rate of binding between interacting elements can determine reaction mechanisms. Coupled folding and binding of IDPs occurs mainly by induced-fit because of the slow folding in the free form, while ligand binding of globular proteins occurs mainly by conformational selection because of rapid conformational change. Protein folding can be regarded as the binding of intramolecular segments accompanied by secondary structure formation. Multi-subdomain proteins fold mainly by the induced-fit (hydrophobic collapse) mechanism, as the connection of interacting segments enhances the binding (compaction) rate. Fewer hydrophobic residues in small proteins reduce the intramolecular binding rate, resulting in the nucleation–condensation mechanism. Thus, the folding and binding of globular proteins and IDPs obey the same general principle, suggesting that the coarse-grained, statistical mechanical model of protein folding is promising for a unified theoretical description of all mechanisms.
“…The Wako-Saitô-Muñoz-Eaton (WSME) model is one such statistical mechanical model that was first developed by Wako and Saitô ( Wako and Saito, 1978a , Wako and Saito, 1978b ), discussed in detail by Gō and Abe ( Go and Abe, 1981 , Abe and Go, 1981 ), and then later independently developed by Muñoz and Eaton (1999) . Originally seen as a physical tool to predict the folding rates of proteins from three-dimensional structures ( Muñoz and Eaton, 1999 , Henry and Eaton, 2004 ), the model has expanded its scope to quantitatively analyze folding behaviors of folded globular domains ( Bruscolini and Naganathan, 2011 , Garcia-Mira et al., 2002 , Narayan and Naganathan, 2014 , Narayan and Naganathan, 2017 , Narayan and Naganathan, 2018 , Naganathan and Muñoz, 2014 , Naganathan et al., 2015 , Munshi and Naganathan, 2015 , Rajasekaran et al., 2016 , Narayan et al., 2017 , Itoh and Sasai, 2006 ), repeat proteins ( Faccin et al., 2011 , Sivanandan and Naganathan, 2013 , Hutton et al., 2015 ), disordered proteins (with appropriate controls) ( Naganathan and Orozco, 2013 , Gopi et al., 2015 , Munshi et al., 2018a ), predict and engineer thermodynamic stabilities of proteins via mutations ( Naganathan, 2012 , Naganathan, 2013b , Rajasekaran et al., 2017 ) and entropic effects ( Rajasekaran et al., 2016 ), model allosteric transitions ( Itoh and Sasai, 2011 , Sasai et al., 2016 ), protein-DNA binding ( Munshi et al., 2018b ), quantifying folding pathways at different levels of resolution ( Henry et al., 2013 , Kubelka et al., 2008 , Gopi et al., 2017 ), force-spectroscopic measurements ( Imparato et al., 2007 ) and even crowding effects ( Caraglio and Pelizzola, 2012 ). Fig.…”
Statistical mechanical models that afford an intermediate resolution between macroscopic chemical models and all-atom simulations have been successful in capturing folding behaviors of many small single-domain proteins. However, the applicability of one such successful approach, the Wako-Saitô-Muñoz-Eaton (WSME) model, is limited by the size of the protein as the number of conformations grows exponentially with protein length. In this work, we surmount this size limitation by introducing a novel approximation that treats stretches of 3 or 4 residues as blocks, thus reducing the phase space by nearly three orders of magnitude. The performance of the ‘bWSME’ model is validated by comparing the predictions for a globular enzyme (RNase H) and a repeat protein (IκBα), against experimental observables and the model without block approximation. Finally, as a proof of concept, we predict the free-energy surface of the 370-residue, multi-domain maltose binding protein and identify an intermediate in good agreement with single-molecule force-spectroscopy measurements. The bWSME model can thus be employed as a quantitative predictive tool to explore the conformational landscapes of large proteins, extract the structural features of putative intermediates, identify parallel folding paths, and thus aid in the interpretation of both ensemble and single-molecule experiments.
“…The Wako–Saitô–Muñoz–Eaton (WSME) model is promising for describing protein-folding reactions [ 17 ]. The WSME model is a coarse-grained model of proteins based on a simple and elementary statistical mechanical theory and can readily calculate free-energy landscapes using the 3D native structures of proteins [ 13 , 18 , 19 , 20 ].…”
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
