scholarly journals Funnels, pathways, and the energy landscape of protein folding: A synthesis

1995 ◽  
Vol 21 (3) ◽  
pp. 167-195 ◽  
Author(s):  
Joseph D. Bryngelson ◽  
José Nelson Onuchic ◽  
Nicholas D. Socci ◽  
Peter G. Wolynes
Keyword(s):  
Protein Folding ◽  
Energy Landscape

scholarly journals Cooperativity and modularity in protein folding

2016 ◽  
Author(s):  
Masaki Sasai ◽  
George Chikenji ◽  
Tomoki P. Terada
Keyword(s):  
Protein Folding ◽  
Mechanical Model ◽  
Energy Landscape ◽  
Native Conformation ◽  
Folding Nucleus ◽  
Modern Methods ◽  
Complex Topology ◽  
Statistical Mechanical Model ◽  
Statistical Mechanical ◽  
Dynamical Features

AbstractA 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. Using the WSME and other related models, Saitô emphasized the importance of the hierarchical pathway in protein folding; folding starts with the creation of contiguous segments having a native-like configuration and proceeds as growth and coalescence of these segments. The ϕ-values calculated for barnase with the WSME model suggested that segments contributing to the folding nucleus are similar to the structural modules defined by the pattern of native atomic contacts. The WSME model was extended to explain folding of multi-domain proteins having a complex topology, which opened the way to comprehensively understanding the folding process of multi-domain proteins. The WSME model was also extended to describe allosteric transitions, indicating that the allosteric structural movement does not occur as a deterministic sequential change between two conformations but as a stochastic diffusive motion over the dynamically changing energy landscape. Statistical mechanical viewpoint on folding, as highlighted by the WSME model, has been renovated in the context of modern methods and ideas, and will continue to provide insights on equilibrium and dynamical features of proteins.

scholarly journals Computational Protein Stabilization Can Affect Folding Energy Landscapes and Lead to Domain-Swapped Dimers

2021 ◽  
Author(s):  
Klara Markova ◽  
Antonin Kunka ◽  
Klaudia Chmelova ◽  
Martin Havlasek ◽  
Petra Babkova ◽  
...  
Keyword(s):  
Protein Folding ◽  
Protein Design ◽  
Energy Landscape ◽  
Single Point ◽  
Three Dimensional ◽  
Protein Stabilization ◽  
Dimensional Structure ◽  
Evolutionary Analysis ◽  
Folding Energy

<p>The functionality of a protein depends on its unique three-dimensional structure, which is a result of the folding process when the nascent polypeptide follows a funnel-like energy landscape to reach a global energy minimum. Computer-encoded algorithms are increasingly employed to stabilize native proteins for use in research and biotechnology applications. Here, we reveal a unique example where the computational stabilization of a monomeric α/β-hydrolase enzyme (<i>T</i><sub>m</sub> = 73.5°C; Δ<i>T</i><sub>m</sub> > 23°C) affected the protein folding energy landscape. Introduction of eleven single-point stabilizing mutations based on force field calculations and evolutionary analysis yielded catalytically active domain-swapped intermediates trapped in local energy minima. Crystallographic structures revealed that these stabilizing mutations target cryptic hinge regions and newly introduced secondary interfaces, where they make extensive non-covalent interactions between the intertwined misfolded protomers. The existence of domain-swapped dimers in a solution is further confirmed experimentally by data obtained from SAXS and crosslinking mass spectrometry. Unfolding experiments showed that the domain-swapped dimers can be irreversibly converted into native-like monomers, suggesting that the domain-swapping occurs exclusively <i>in vivo</i>. Our findings uncovered hidden protein-folding consequences of computational protein design, which need to be taken into account when applying a rational stabilization to proteins of biological and pharmaceutical interest.</p>

scholarly journals Computational Protein Stabilization Can Affect Folding Energy Landscapes and Lead to Domain-Swapped Dimers

2021 ◽  
Author(s):  
Klara Markova ◽  
Antonin Kunka ◽  
Klaudia Chmelova ◽  
Martin Havlasek ◽  
Petra Babkova ◽  
...  
Keyword(s):  
Protein Folding ◽  
Protein Design ◽  
Energy Landscape ◽  
Single Point ◽  
Three Dimensional ◽  
Protein Stabilization ◽  
Dimensional Structure ◽  
Evolutionary Analysis ◽  
Folding Energy

<p>The functionality of a protein depends on its unique three-dimensional structure, which is a result of the folding process when the nascent polypeptide follows a funnel-like energy landscape to reach a global energy minimum. Computer-encoded algorithms are increasingly employed to stabilize native proteins for use in research and biotechnology applications. Here, we reveal a unique example where the computational stabilization of a monomeric α/β-hydrolase enzyme (<i>T</i><sub>m</sub> = 73.5°C; Δ<i>T</i><sub>m</sub> > 23°C) affected the protein folding energy landscape. Introduction of eleven single-point stabilizing mutations based on force field calculations and evolutionary analysis yielded catalytically active domain-swapped intermediates trapped in local energy minima. Crystallographic structures revealed that these stabilizing mutations target cryptic hinge regions and newly introduced secondary interfaces, where they make extensive non-covalent interactions between the intertwined misfolded protomers. The existence of domain-swapped dimers in a solution is further confirmed experimentally by data obtained from SAXS and crosslinking mass spectrometry. Unfolding experiments showed that the domain-swapped dimers can be irreversibly converted into native-like monomers, suggesting that the domain-swapping occurs exclusively <i>in vivo</i>. Our findings uncovered hidden protein-folding consequences of computational protein design, which need to be taken into account when applying a rational stabilization to proteins of biological and pharmaceutical interest.</p>

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