scholarly journals Conformational Landscape Reduction of a Dynamic 29-Residue Peptide by a Perfluoroaromatic Small Molecule

2020 ◽  
Author(s):  
ethan evans
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Dynamic Systems ◽  
Biochemical Properties ◽  
State Dependent ◽  
C Terminus ◽  
Explicit Solvent ◽  
Conformational Landscape

Conformationally dynamic peptides and proteins display both important biochemical properties and present a challenge for computational modeling. Characterizing the accessible structural landscape represents one route to understand their function with molecular level detail. We characterize a self-labeling 29-residue peptide, MP01-Gen4, that undergoes structural alterations in the presence of a perfluoroaromatic reaction partner. Replica exchange molecular dynamics (REMD) shows MP01 to access a broad set of states, that microsecond-long explicit solvent simulations only minimally sample. REMD and structural network analysis find an altered and reduced conformational landscape when MP01 interacts non-covalently or is covalently attached to the perfluoroaromatic small molecule. Residues throughout the peptide, notably at the C-terminus, interact with the small molecule in conformational state-dependent manners. The results help explain and generate hypotheses for experimental observations including the importance of flexibility and the role of the N- and C-terminal regions, both of which are distant from the active cysteine. The simulations highlight the importance of substantial sampling in minimally stabilized, conformationally dynamic systems and supplies a case study for small molecule-mediated, peptide conformational changes.<br>

scholarly journals Conformational Landscape Reduction of a Dynamic 29-Residue Peptide by a Perfluoroaromatic Small Molecule

2020 ◽  
Author(s):  
ethan evans
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Dynamic Systems ◽  
Biochemical Properties ◽  
State Dependent ◽  
C Terminus ◽  
Explicit Solvent ◽  
Conformational Landscape

Conformationally dynamic peptides and proteins display both important biochemical properties and present a challenge for computational modeling. Characterizing the accessible structural landscape represents one route to understand their function with molecular level detail. We characterize a self-labeling 29-residue peptide, MP01-Gen4, that undergoes structural alterations in the presence of a perfluoroaromatic reaction partner. Replica exchange molecular dynamics (REMD) shows MP01 to access a broad set of states, that microsecond-long explicit solvent simulations only minimally sample. REMD and structural network analysis find an altered and reduced conformational landscape when MP01 interacts non-covalently or is covalently attached to the perfluoroaromatic small molecule. Residues throughout the peptide, notably at the C-terminus, interact with the small molecule in conformational state-dependent manners. The results help explain and generate hypotheses for experimental observations including the importance of flexibility and the role of the N- and C-terminal regions, both of which are distant from the active cysteine. The simulations highlight the importance of substantial sampling in minimally stabilized, conformationally dynamic systems and supplies a case study for small molecule-mediated, peptide conformational changes.<br>

scholarly journals Epigenetic modification in the expression of p73 p73 - epigenetic target for anticancer therapy

2019 ◽  
Vol 13 (2) ◽  
Author(s):  
Faiza Naseer ◽  
Mohammad Saleem
Keyword(s):  
Conformational Changes ◽  
Posttranslational Modifications ◽  
Epigenetic Modification ◽  
Amino Acid Residues ◽  
P53 Family ◽  
After Effects ◽  
Cycle Arrest ◽  
C Terminus ◽  
Upstream Promoter

A p73 is a new member of p53 family of transcription factor, having two types. First is TAp73, transcriptionally active and expressed via upstream promoter as a tumor suppressor and vital apoptotic inductor, it also has a key role in cell cycle arrest/differentiation and Second is ΔNp73 that is transcriptionally inactive and expressed via downstream regulator as oncogenes. Both types are expressed in various isoforms, which originate from alternative splicing events at the C-terminus. Upon DNA damage, posttranslational modifications cause conformational changes in various amino acid residues via induction or inhibition of various proteins, which are present in the structural domains of p73. These modifications may cause up- or down-regulation of p73 expression levels, as well as alters the transcriptional activity and/or stability of the protein. In this review, we have made an effort to assemble all existing data regarding the role of p73, its modification and after effects in cancer.

scholarly journals Role of C-Terminal Cysteine Residues of Aspergillus fumigatus Allergen Asp f 4 in Immunoglobulin E Binding

2004 ◽  
Vol 11 (2) ◽  
pp. 261-265 ◽  
Author(s):  
Harikrishnan Ramachandran ◽  
Banani Banerjee ◽  
Paul A. Greenberger ◽  
Kevin J. Kelly ◽  
Jordan N. Fink ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Conformational Changes ◽  
Immunoglobulin E ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Allergic Diseases ◽  
Cysteine Residues ◽  
Conformational Structure ◽  
C Terminus ◽  
Function Relationship

ABSTRACT Among the several allergens cloned and expressed from Aspergillus fumigatus, Asp f 4 is a major one associated with allergic bronchopulmonary aspergillosis (ABPA). The structure-function relationship of allergens is important in understanding the immunopathogenesis, diagnosis, and treatment of allergic diseases. These include the epitopes, conformational or linear, deletion of the N or C terminus or both N and C termini, and glycosylation or nonglycosylation, all of which affect immune responses. Similarly, the role of cysteine residues present in allergens may yield useful information regarding the conformational structure of allergens and the immunoglobulin E (IgE) epitope interaction. Such information may help in developing new strategies towards immunotherapy. In order to define the role of cysteine in the interaction of the antibody with Asp f 4, we have constructed mutants by selectively deleting cysteine residues from the C-terminal region of the Asp f 4. Immunological evaluation of these engineered recombinant constructs was conducted by using sera from patients with ABPA, Aspergillus skin test-positive asthmatics, and healthy controls. The results demonstrate strong IgE binding with Asp f 4 and two truncated mutants, Asp f 41-234 (amino acids [aa] 1 to 234) and Asp f 41-241 (aa 1 to 241), while another mutant, Asp f 41-196 (aa 1 to 196), showed reactivity with fewer patients. The result suggests that deletion of cysteines and the alteration of IgE epitopes at the C-terminal end resulted in conformational changes, which may have a potential role in the immunomodulation of the disease.

scholarly journals The role of the C terminus of the SNARE protein SNAP-25 in fusion pore opening and a model for fusion pore mechanics

2008 ◽  
Vol 105 (40) ◽  
pp. 15388-15392 ◽  
Author(s):  
Qinghua Fang ◽  
Khajak Berberian ◽  
Liang-Wei Gong ◽  
Ismail Hafez ◽  
Jakob B. Sørensen ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Mechanistic Model ◽  
Snare Complex ◽  
Fusion Pore ◽  
Snare Protein ◽  
C Terminus ◽  
Target Membrane ◽  
Pore Opening ◽  
Fusion Pores

Formation of a fusion pore between a vesicle and its target membrane is thought to involve the so-called SNARE protein complex. However, there is no mechanistic model explaining how the fusion pore is opened by conformational changes in the SNARE complex. It has been suggested that C-terminal zipping triggers fusion pore opening. A SNAP-25 mutant named SNAP-25Δ9 (lacking the last nine C-terminal residues) should lead to a less-tight C-terminal zipping. Single exocytotic events in chromaffin cells expressing this mutant were characterized by carbon fiber amperometry and cell-attached patch capacitance measurements. Cells expressing SNAP-25Δ9 displayed smaller amperometric “foot-current” currents, reduced fusion pore conductances, and lower fusion pore expansion rates. We propose that SNARE/lipid complexes form proteolipid fusion pores. Fusion pores involving the SNAP-25Δ9 mutant will be less tightly zipped and may lead to a longer fusion pore structure, consistent with the observed decrease of fusion pore conductance.

scholarly journals Phosphorylation and O-GlcNAcylation of the PHF-1 Epitope of Tau Protein Induce Local Conformational Changes of the C-Terminus and Modulate Tau Self-Assembly Into Fibrillar Aggregates

2021 ◽  
Vol 14 ◽  
Author(s):  
François-Xavier Cantrelle ◽  
Anne Loyens ◽  
Xavier Trivelli ◽  
Oliver Reimann ◽  
Clément Despres ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Tau Protein ◽  
Posttranslational Modifications ◽  
Self Assembly ◽  
Critical Role ◽  
Small Peptides ◽  
C Terminus ◽  
The Impact

Phosphorylation of the neuronal microtubule-associated Tau protein plays a critical role in the aggregation process leading to the formation of insoluble intraneuronal fibrils within Alzheimer’s disease (AD) brains. In recent years, other posttranslational modifications (PTMs) have been highlighted in the regulation of Tau (dys)functions. Among these PTMs, the O-β-linked N-acetylglucosaminylation (O-GlcNAcylation) modulates Tau phosphorylation and aggregation. We here focus on the role of the PHF-1 phospho-epitope of Tau C-terminal domain that is hyperphosphorylated in AD (at pS396/pS404) and encompasses S400 as the major O-GlcNAc site of Tau while two additional O-GlcNAc sites were found in the extreme C-terminus at S412 and S413. Using high resolution NMR spectroscopy, we showed that the O-GlcNAc glycosylation reduces phosphorylation of PHF-1 epitope by GSK3β alone or after priming by CDK2/cyclin A. Furthermore, investigations of the impact of PTMs on local conformation performed in small peptides highlight the role of S404 phosphorylation in inducing helical propensity in the region downstream pS404 that is exacerbated by other phosphorylations of PHF-1 epitope at S396 and S400, or O-GlcNAcylation of S400. Finally, the role of phosphorylation and O-GlcNAcylation of PHF-1 epitope was probed in in-vitro fibrillization assays in which O-GlcNAcylation slows down the rate of fibrillar assembly while GSK3β phosphorylation stimulates aggregation counteracting the effect of glycosylation.

scholarly journals Performance of a reinforced embankment on a sensitive Champlain clay deposit

2012 ◽  
Vol 49 (8) ◽  
pp. 917-927 ◽  
Author(s):  
Chalermpol Taechakumthorn ◽  
R. Kerry Rowe
Keyword(s):  
Field Data ◽  
Pore Water Pressure ◽  
Water Pressure ◽  
Clay Deposit ◽  
Soil Model ◽  
State Dependent ◽  
Damage Law ◽  
Test Embankment

An existing elastoviscoplastic constitutive model is modified using concepts of the state-dependent fluidity parameters and the damage law, to incorporate the effect of soil structure and its destructuration. The model is employed to simulate the performance of a well-documented case study of the reinforced test embankment constructed over a sensitive Champlain clay deposit at Saint Alban, Quebec. The finite element calculations, using both the original (nonstructured) and modified (structured) elastoviscoplastic soil models, are compared with the observed field data from a test embankment brought to failure. The results from the structured elastoviscoplastic soil model show better agreements with the field data when compared with those analyzed using the nonstructured elastoviscoplastic soil model. The modified model captures many features of the reinforced embankment behaviour, such as vertical settlement, excess pore-water pressure responses, and reinforcement force. However, they also reveal the fact that another important characteristic of the natural clay deposit — anisotropy — needs to be considered to provide an adequate prediction of horizontal deformations. The role of geosynthetic reinforcement and its viscosity on short-term responses of the reinforced embankment examined in this study is also discussed

scholarly journals Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant

Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1240
Author(s):  
Stepan Timr ◽  
Fabio Sterpone
Keyword(s):  
Superoxide Dismutase ◽  
Conformational Changes ◽  
State Of The Art ◽  
Model System ◽  
Superoxide Dismutase 1 ◽  
Ambient Temperatures ◽  
Conformational Landscape ◽  
The Stability ◽  
Lateral Sclerosis

In this work, we investigate the β-barrel of superoxide dismutase 1 (SOD1) in a mutated form, the isoleucine 35 to alanine (I35A) mutant, commonly used as a model system to decipher the role of the full-length apoSOD1 protein in amyotrophic lateral sclerosis (ALS). It is known from experiments that the mutation reduces the stability of the SOD1 barrel and makes it largely unfolded in the cell at 37 degrees Celsius. We deploy state-of-the-art computational machinery to examine the thermal destabilization of the I35A mutant by comparing two widely used force fields, Amber a99SB-disp and CHARMM36m. We find that only the latter force field, when combined with the Replica Exchange with Solute Scaling (REST2) approach, reproduces semi-quantitatively the experimentally observed shift in the melting between the original and the mutated SOD1 barrel. In addition, we analyze the unfolding process and the conformational landscape of the mutant, finding these largely similar to those of the wildtype. Nevertheless, we detect an increased presence of partially misfolded states at ambient temperatures. These states, featuring conformational changes in the region of the β-strands β4−β6, might provide a pathway for nonnative aggregation.

Role of spectrin in membrane fusion and in shape change of human erythrocyte ghost

1978 ◽  
Vol 36 (2) ◽  
pp. 328-329
Author(s):  
Hideo Hayashi ◽  
Yoshikazu Hirai ◽  
John T. Penniston
Keyword(s):  
Conformational Changes ◽  
Human Erythrocyte ◽  
Shape Change ◽  
Membrane Surface ◽  
Slight Modification ◽  
Active Role ◽  
Main Role ◽  
Bank Blood ◽  
Human Erythrocyte Ghost

Spectrin is a membrane associated protein most of which properties have been tentatively elucidated. A main role of the protein has been assumed to give a supporting structure to inside of the membrane. As reported previously, however, the isolated spectrin molecule underwent self assemble to form such as fibrous, meshwork, dispersed or aggregated arrangements depending upon the buffer suspended and was suggested to play an active role in the membrane conformational changes. In this study, the role of spectrin and actin was examined in terms of the molecular arrangements on the erythrocyte membrane surface with correlation to the functional states of the ghosts.Human erythrocyte ghosts were prepared from either freshly drawn or stocked bank blood by the method of Dodge et al with a slight modification as described before. Anti-spectrin antibody was raised against rabbit by injection of purified spectrin and partially purified.

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