Role of Topology in the Cooperative Collapse of the Protein Core in the Sequential Collapse Model. Folding Pathway of α-Lactalbumin and Hen Lysozyme

2001 ◽  
Vol 105 (14) ◽  
pp. 2874-2880 ◽  
Author(s):  
Fernando Bergasa-Caceres ◽  
Herschel A. Rabitz
Keyword(s):  
Folding Pathway ◽  
Protein Core ◽  
Collapse Model

scholarly journals Identification of Two Early Folding Stage Prion Non-Local Contacts Suggested to Serve as Key Steps in Directing the Final Fold to Be Either Native or Pathogenic

2021 ◽  
Vol 22 (16) ◽  
pp. 8619
Author(s):  
Fernando Bergasa-Caceres ◽  
Herschel A. Rabitz
Keyword(s):  
Prion Protein ◽  
Molten Globule ◽  
Folding Pathway ◽  
Initiation Point ◽  
Local Contact ◽  
Collapse Model ◽  
Non Local ◽  
Key Steps ◽  
Potential Initiation

The initial steps of the folding pathway of the C-terminal domain of the murine prion protein mPrP(90–231) are predicted based on the sequential collapse model (SCM). A non-local dominant contact is found to form between the connecting region between helix 1 and b-sheet 1 and the C-terminal region of helix 3. This non-local contact nucleates the most populated molten globule-like intermediate along the folding pathway. A less stable early non-local contact between segments 120–124 and 179–183, located in the middle of helix 2, promotes the formation of a less populated molten globule-like intermediate. The formation of the dominant non-local contact constitutes an example of the postulated Nature’s Shortcut to the prion protein collapse into the native structure. The possible role of the less populated molten globule-like intermediate is explored as the potential initiation point for the folding for three pathogenic mutants (T182A, I214V, and Q211P in mouse prion numbering) of the prion protein.

Folding mechanisms of group I ribozymes: role of stability and contact order

2002 ◽  
Vol 30 (6) ◽  
pp. 1166-1169 ◽  
Author(s):  
S. A. Woodson
Keyword(s):  
Catalytic Activity ◽  
Rna Folding ◽  
Three Dimensional ◽  
Model System ◽  
Folding Pathway ◽  
Primary Sequence ◽  
Rna Molecules ◽  
Contact Order ◽  
Group I

The mechanism by which RNA molecules assemble into unique three-dimensional conformations is important for understanding their function, regulation and interactions with substrates. The Tetrahymena group I ribozyme is an excellent model system for understanding RNA folding mechanisms, because the catalytic activity of the native RNA is easily measured. Folding of the Tetrahymena ribozyme is dominated by intermediates in which the stable P4-P6 domain is correctly formed, but the P3-P9 domain is partially misfolded. The propensity of the RNA to misfold depends on the relative stability of native and non-native interactions. Circular permutation of the Tetrahymena ribozyme shows that the distance in the primary sequence between native interactions also influences the folding pathway.

scholarly journals The Role of E27-K31 and E56-K10 Salt-Bridge Pairs in the Unfolding Mechanism of the B1 Domain of Protein G

2018 ◽  
Vol 18 (1) ◽  
pp. 186
Author(s):  
Tony Ibnu Sumaryada ◽  
Kania Nur Sawitri ◽  
Setyanto Tri Wahyudi
Keyword(s):  
Tertiary Structure ◽  
Salt Bridge ◽  
Protein G ◽  
Core Collapse ◽  
Hydrophobic Core ◽  
B1 Domain ◽  
Collapse Model ◽  
Α Helix ◽  
Dynamics Simulations

Molecular dynamics simulations of the B1 fragment of protein G (56 residues) have been performed at 325, 350, 375, 400, 450 and 500 K for 10 ns. An analysis of its structural and energetic parameters has indicated that the unfolding process of the GB1 protein begins at 900 ps of a 500-K simulation. The unfolding process is initiated when hydrogen bonds in the hydrophobic core region are broken; it continues with the α-helix transformation into coils and turns and ends with the destruction of the β-hairpins. These unfolding events are consistent with the hybrid model of the protein folding/unfolding mechanism, which is a compromise between the hydrophobic core collapse model and the zipper model. Salt-bridge pairs were found to play an important role in the unfolding process by maintaining the integrity of the tertiary structure of the protein. The breaking (or disappearance) of the salt-bridge pairs E27–K31 (in the α-helix) and E56–K10 (connecting β4 and β1) has resulted in the destruction of secondary structures and indicates the beginning of the unfolding process. Our results also suggest that the unfolding process in this simulation was not a complete denaturation of the protein because some β-hairpins remained

scholarly journals Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome

2019 ◽  
Author(s):  
Evan J. Worden ◽  
Xiangbin Zhang ◽  
Cynthia Wolberger
Keyword(s):  
Histone Methylation ◽  
Structural Basis ◽  
Structural Rearrangements ◽  
H3k4 Methylation ◽  
Core Complex ◽  
Histone H2b ◽  
Protein Core ◽  
The Face ◽  
Histone H3k4

ABSTRACTMethylation of histone H3K4 is a hallmark of actively transcribed genes that depends on mono-ubiquitination of histone H2B (H2B-Ub). H3K4 methylation in yeast is catalyzed by Set1, the methyltransferase subunit of COMPASS. We report here the cryo-EM structure of a six-protein core COMPASS subcomplex, which can methylate H3K4 and be stimulated by H2B-Ub, bound to a ubiquitinated nucleosome. Our structure shows that COMPASS spans the face of the nucleosome, recognizing ubiquitin on one face of the nucleosome and methylating H3 on the opposing face. As compared to the structure of the isolated core complex, Set1 undergoes multiple structural rearrangements to cement interactions with the nucleosome and with ubiquitin. The critical Set1 RxR motif adopts a helix that mediates bridging contacts between the nucleosome, ubiquitin and COMPASS. The structure provides a framework for understanding mechanisms of trans-histone cross-talk and the dynamic role of H2B ubiquitination in stimulating histone methylation.

scholarly journals The role of the nucleosome acidic patch in modulating higher order chromatin structure

2013 ◽  
Vol 10 (82) ◽  
pp. 20121022 ◽  
Author(s):  
Anna A. Kalashnikova ◽  
Mary E. Porter-Goff ◽  
Uma M. Muthurajan ◽  
Karolin Luger ◽  
Jeffrey C. Hansen
Keyword(s):  
Higher Order ◽  
Folding Pathway ◽  
Computational Studies ◽  
Biological Functions ◽  
Histone H4 ◽  
Chromatin Fibre ◽  
Chromatin Folding ◽  
Non Covalent Interactions ◽  
Covalent Interactions

Higher order folding of chromatin fibre is mediated by interactions of the histone H4 N-terminal tail domains with neighbouring nucleosomes. Mechanistically, the H4 tails of one nucleosome bind to the acidic patch region on the surface of adjacent nucleosomes, causing fibre compaction. The functionality of the chromatin fibre can be modified by proteins that interact with the nucleosome. The co-structures of five different proteins with the nucleosome (LANA, IL-33, RCC1, Sir3 and HMGN2) recently have been examined by experimental and computational studies. Interestingly, each of these proteins displays steric, ionic and hydrogen bond complementarity with the acidic patch, and therefore will compete with each other for binding to the nucleosome. We first review the molecular details of each interface, focusing on the key non-covalent interactions that stabilize the protein–acidic patch interactions. We then propose a model in which binding of proteins to the nucleosome disrupts interaction of the H4 tail domains with the acidic patch, preventing the intrinsic chromatin folding pathway and leading to assembly of alternative higher order chromatin structures with unique biological functions.

scholarly journals The Promise of Mutation Resistant Drugs for SARS-CoV-2 that Interdict in the Folding of the Spike Protein Receptor Binding Domain

COVID ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 288-302
Author(s):  
Fernando Bergasa-Caceres ◽  
Herschel A. Rabitz
Keyword(s):  
Receptor Binding ◽  
Drug Target ◽  
Binding Domain ◽  
Spike Protein ◽  
Folding Pathway ◽  
Receptor Binding Domain ◽  
Double Mutation ◽  
Therapeutic Drugs ◽  
Protein Receptor ◽  
Collapse Model

In recent work, we proposed that effective therapeutic drugs aimed at treating the SARS-CoV-2 infection could be developed based on interdicting in the early steps of the folding pathway of key viral proteins, including the receptor binding domain (RBD) of the spike protein. In order to provide for a drug target on the protein, the earliest contact-formation event along the dominant folding pathway of the RBD spike protein was predicted employing the Sequential Collapse Model (SCM). The segments involved in the predicted earliest contact were suggested to provide optimal folding interdiction target regions (FITRs) for potential therapeutic drugs, with a focus on folding interdicting peptides (FIPs). In this paper, we extend our analysis to include 13 known single mutations of the RBD spike protein as well as the triple mutation B1.351 and the recent double mutation B1.617.2. The results show that the location of the FITR does not change in any of the 15 studied mutations, providing for a mutation-resistant drug design strategy for the RBD-spike protein.

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