An Effective Approach for Identifying Evolving Three-Dimensional Structural Motifs in Protein Folding Data

2020 ◽

Vol 26 (42) ◽

pp. 7537-7554 ◽

Cited By ~ 1

Author(s):

Juan Zeng ◽

Zunnan Huang

Keyword(s):

Protein Folding ◽

Posttranslational Modifications ◽

Three Dimensional ◽

Rational Drug Design ◽

Basic Knowledge ◽

Sequence Evolution ◽

3D Structures ◽

Folding Mechanism ◽

Cellular Environment ◽

Environment Temperature

Background: The rapidly increasing number of known protein sequences calls for more efficient methods to predict the Three-Dimensional (3D) structures of proteins, thus providing basic knowledge for rational drug design. Understanding the folding mechanism of proteins is valuable for predicting their 3D structures and for designing proteins with new functions and medicinal applications. Levinthal’s paradox is that although the astronomical number of conformations possible even for proteins as small as 100 residues cannot be fully sampled, proteins in nature normally fold into the native state within timescales ranging from microseconds to hours. These conflicting results reveal that there are factors in organisms that can assist in protein folding. Methods: In this paper, we selected a crowded cell-like environment and temperature, and the top three Posttranslational Modifications (PTMs) as examples to show that Levinthal’s paradox does not reflect the folding mechanism of proteins. We then revealed the effects of these factors on protein folding. Results: The results summarized in this review indicate that a crowded cell-like environment, temperature, and the top three PTMs reshape the Free Energy Landscapes (FELs) of proteins, thereby regulating the folding process. The balance between entropy and enthalpy is the key to understanding the effect of the crowded cell-like environment and PTMs on protein folding. In addition, the stability/flexibility of proteins is regulated by temperature. Conclusion: This paper concludes that the cellular environment could directly intervene in protein folding. The long-term interactions of the cellular environment and sequence evolution may enable proteins to fold efficiently. Therefore, to correctly understand the folding mechanism of proteins, the effect of the cellular environment on protein folding should be considered.

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Protein Folding: Search for Basic Physical Models

The Scientific World JOURNAL ◽

10.1100/tsw.2003.50 ◽

2003 ◽

Vol 3 ◽

pp. 623-635 ◽

Cited By ~ 3

Author(s):

Ivan Y. Torshin ◽

Robert W. Harrison

Keyword(s):

Protein Folding ◽

Tertiary Structure ◽

Three Dimensional ◽

Physical Models ◽

Dimensional Structure ◽

Computational Techniques ◽

Linear Sequence ◽

Physical Forces

How a unique three-dimensional structure is rapidly formed from the linear sequence of a polypeptide is one of the important questions in contemporary science. Apart from biological context ofin vivoprotein folding (which has been studied only for a few proteins), the roles of the fundamental physical forces in thein vitrofolding remain largely unstudied. Despite a degree of success in using descriptions based on statistical and/or thermodynamic approaches, few of the current models explicitly include more basic physical forces (such as electrostatics and Van Der Waals forces). Moreover, the present-day models rarely take into account that the protein folding is, essentially, a rapid process that produces a highly specific architecture. This review considers several physical models that may provide more direct links between sequence and tertiary structure in terms of the physical forces. In particular, elaboration of such simple models is likely to produce extremely effective computational techniques with value for modern genomics.

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

10.26434/chemrxiv.13634021.v1 ◽

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

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 (Tm = 73.5°C; ΔTm > 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 in vivo. 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.

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

10.26434/chemrxiv.13634021 ◽

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

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 (Tm = 73.5°C; ΔTm > 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 in vivo. 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.

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Biophysical Insight into Protein Folding, Aggregate Formation and its Inhibition Strategies

Protein and Peptide Letters ◽

10.2174/0929866528666211125114421 ◽

2021 ◽

Vol 28 ◽

Author(s):

Syed Mohammad Zakariya ◽

Aiman Zehr ◽

Rizwan Hasan Khan

Keyword(s):

Protein Folding ◽

Amyloid Fibrils ◽

Three Dimensional ◽

The Body ◽

Aggregate Formation ◽

Structural Characterisation ◽

Current Scenario ◽

Underlying Mechanisms ◽

Quality Control Mechanism ◽

Insight Into

: The failure of protein to correctly fold into its functional and unique three dimensional form leads to misfolded or partially folded protein. When these rogue proteins and polypeptides escape the quality control mechanism within the body, they result in aberrant aggregation of proteins into characteristic amyloid fibrils. This is the main cause for the number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s and Huntington’s diseases. This review aims to summarise the underlying mechanisms of protein folding, misfolding and aggregation. It also highlights the recent technologies for the structural characterisation and detection of amyloid fibrils in addition to the various factors responsible for the aggregate formation and the strategies to combat the aggregation process. Besides, the journey from origin to the current scenario of protein aggregation is also concisely discussed.

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The Ensemble of Conformations of Antifreeze Glycoproteins (AFGP8): A Study Using Nuclear Magnetic Resonance Spectroscopy

Biomolecules ◽

10.3390/biom9060235 ◽

2019 ◽

Vol 9 (6) ◽

pp. 235

Author(s):

Cheenou Her ◽

Yin Yeh ◽

Viswanathan V. Krishnan

Keyword(s):

Nuclear Magnetic Resonance ◽

Magnetic Resonance ◽

Three Dimensional ◽

Random Coil ◽

The Arctic ◽

Native Structure ◽

Antifreeze Glycoproteins ◽

Structural Motifs ◽

Ice Surface ◽

Nuclear Magnetic

The primary sequence of antifreeze glycoproteins (AFGPs) is highly degenerate, consisting of multiple repeats of the same tripeptide, Ala–Ala–Thr*, in which Thr* is a glycosylated threonine with the disaccharide beta-d-galactosyl-(1,3)-alpha-N-acetyl-d-galactosamine. AFGPs seem to function as intrinsically disordered proteins, presenting challenges in determining their native structure. In this work, a different approach was used to elucidate the three-dimensional structure of AFGP8 from the Arctic cod Boreogadus saida and the Antarctic notothenioid Trematomus borchgrevinki. Dimethyl sulfoxide (DMSO), a non-native solvent, was used to make AFGP8 less dynamic in solution. Interestingly, DMSO induced a non-native structure, which could be determined via nuclear magnetic resonance (NMR) spectroscopy. The overall three-dimensional structures of the two AFGP8s from two different natural sources were different from a random coil ensemble, but their “compactness” was very similar, as deduced from NMR measurements. In addition to their similar compactness, the conserved motifs, Ala–Thr*–Pro–Ala and Ala–Thr*–Ala–Ala, present in both AFGP8s, seemed to have very similar three-dimensional structures, leading to a refined definition of local structural motifs. These local structural motifs allowed AFGPs to be considered functioning as effectors, making a transition from disordered to ordered upon binding to the ice surface. In addition, AFGPs could act as dynamic linkers, whereby a short segment folds into a structural motif, while the rest of the AFGPs could still be disordered, thus simultaneously interacting with bulk water molecules and the ice surface, preventing ice crystal growth.

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Backbone dihedral angles prediction servers for protein early-stage structure prediction

Bio-Algorithms and Med-Systems ◽

10.1515/bams-2019-0034 ◽

2019 ◽

Vol 15 (4) ◽

Author(s):

Tomasz Smolarczyk ◽

Katarzyna Stapor ◽

Irena Roterman-Konieczna

Keyword(s):

Protein Folding ◽

Secondary Structure ◽

Protein Function ◽

Structure Prediction ◽

Secondary Structure Prediction ◽

Early Stage ◽

Three Dimensional ◽

Stage Structure ◽

Dihedral Angles ◽

Starting Point

AbstractThree-dimensional protein structure prediction is an important task in science at the intersection of biology, chemistry, and informatics, and it is crucial for determining the protein function. In the two-stage protein folding model, based on an early- and late-stage intermediates, we propose to use state-of-the-art secondary structure prediction servers for backbone dihedral angles prediction and devise an early-stage structure. Early-stage structures are used as a starting point for protein folding simulations, and any errors in this stage affect the final predictions. We have shown that modern secondary structure prediction servers could increase the accuracy of early-stage predictions compared to previously reported models.

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