scholarly journals Analysis of the REJ Module of Polycystin-1 Using Molecular Modeling and Force-Spectroscopy Techniques

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Meixiang Xu ◽  
Liang Ma ◽  
Paul J. Bujalowski ◽  
Feng Qian ◽  
R. Bryan Sutton ◽  
...  
Keyword(s):  
Amino Acids ◽  
Molecular Modeling ◽  
Single Molecule ◽  
Mechanical Stability ◽  
Transmembrane Protein ◽  
Genetic Diseases ◽  
Force Spectroscopy ◽  
Modeling Analysis ◽  
Life Threatening ◽  
Autosomal Dominant Polycystic Kidney

Polycystin-1 is a large transmembrane protein, which, when mutated, causes autosomal dominant polycystic kidney disease, one of the most common life-threatening genetic diseases that is a leading cause of kidney failure. The REJ (receptor for egg lelly) module is a major component of PC1 ectodomain that extends to about 1000 amino acids. Many missense disease-causing mutations map to this module; however, very little is known about the structure or function of this region. We used a combination of homology molecular modeling, protein engineering, steered molecular dynamics (SMD) simulations, and single-molecule force spectroscopy (SMFS) to analyze the conformation and mechanical stability of the first ~420 amino acids of REJ. Homology molecular modeling analysis revealed that this region may contain structural elements that have an FNIII-like structure, which we named REJd1, REJd2, REJd3, and REJd4. We found that REJd1 has a higher mechanical stability than REJd2 (~190 pN and 60 pN, resp.). Our data suggest that the putative domains REJd3 and REJd4 likely do not form mechanically stable folds. Our experimental approach opens a new way to systematically study the effects of disease-causing mutations on the structure and mechanical properties of the REJ module of PC1.

Single molecule force spectroscopy reveals that the oxidation state of cobalt ions plays an important role in enhancing the mechanical stability of proteins

Nanoscale ◽  
2019 ◽  
Vol 11 (42) ◽  
pp. 19791-19796 ◽  
Author(s):  
Jiahao Xia ◽  
Jiacheng Zuo ◽  
Hongbin Li
Keyword(s):  
Oxidation State ◽  
Single Molecule ◽  
Mechanical Stability ◽  
Force Spectroscopy ◽  
Metal Chelation ◽  
Single Molecule Force Spectroscopy ◽  
Cobalt Ions

The binding of Co(iii) to the bi-histidine metal chelation site significantly enhances protein's mechanical stability.

scholarly journals Molecular mechanism of extreme mechanostability in a pathogen adhesin

Science ◽  
2018 ◽  
Vol 359 (6383) ◽  
pp. 1527-1533 ◽  
Author(s):  
Lukas F. Milles ◽  
Klaus Schulten ◽  
Hermann E. Gaub ◽  
Rafael C. Bernardi
Keyword(s):  
Single Molecule ◽  
Mechanical Stability ◽  
Force Spectroscopy ◽  
Covalent Bond ◽  
Binding Pocket ◽  
Peptide Backbone ◽  
Human Fibrinogen ◽  
Single Molecule Force Spectroscopy ◽  
Force Microscopy ◽  
Dynamics Simulations

High resilience to mechanical stress is key when pathogens adhere to their target and initiate infection. Using atomic force microscopy–based single-molecule force spectroscopy, we explored the mechanical stability of the prototypical staphylococcal adhesin SdrG, which targets a short peptide from human fibrinogen β. Steered molecular dynamics simulations revealed, and single-molecule force spectroscopy experiments confirmed, the mechanism by which this complex withstands forces of over 2 nanonewtons, a regime previously associated with the strength of a covalent bond. The target peptide, confined in a screwlike manner in the binding pocket of SdrG, distributes forces mainly toward the peptide backbone through an intricate hydrogen bond network. Thus, these adhesins can attach to their target with exceptionally resilient mechanostability, virtually independent of peptide side chains.

scholarly journals Mechanical stability of bivalent transition metal complexes analyzed by single-molecule force spectroscopy

2015 ◽  
Vol 11 ◽  
pp. 817-827 ◽  
Author(s):  
Manuel Gensler ◽  
Christian Eidamshaus ◽  
Maurice Taszarek ◽  
Hans-Ulrich Reissig ◽  
Jürgen P Rabe
Keyword(s):  
Transition Metal Complexes ◽  
Single Molecule ◽  
Mechanical Stability ◽  
Force Spectroscopy ◽  
Model Systems ◽  
Bond Rupture ◽  
Aqueous Environment ◽  
Single Molecule Force Spectroscopy ◽  
Bivalent Transition Metal ◽  
Rupture Behavior

Multivalent biomolecular interactions allow for a balanced interplay of mechanical stability and malleability, and nature makes widely use of it. For instance, systems of similar thermal stability may have very different rupture forces. Thus it is of paramount interest to study and understand the mechanical properties of multivalent systems through well-characterized model systems. We analyzed the rupture behavior of three different bivalent pyridine coordination complexes with Cu2+ in aqueous environment by single-molecule force spectroscopy. Those complexes share the same supramolecular interaction leading to similar thermal off-rates in the range of 0.09 and 0.36 s−1, compared to 1.7 s−1 for the monovalent complex. On the other hand, the backbones exhibit different flexibility, and we determined a broad range of rupture lengths between 0.3 and 1.1 nm, with higher most-probable rupture forces for the stiffer backbones. Interestingly, the medium-flexible connection has the highest rupture forces, whereas the ligands with highest and lowest rigidity seem to be prone to consecutive bond rupture. The presented approach allows separating bond and backbone effects in multivalent model systems.

Using single molecule force spectroscopy to facilitate a rational design of Ca2+-responsive β-roll peptide-based hydrogels

2018 ◽  
Vol 6 (32) ◽  
pp. 5303-5312 ◽  
Author(s):  
Lichao Liu ◽  
Han Wang ◽  
Yueying Han ◽  
Shanshan Lv ◽  
Jianfeng Chen
Keyword(s):  
Mechanical Properties ◽  
Single Molecule ◽  
Rational Design ◽  
Mechanical Stability ◽  
Force Spectroscopy ◽  
Single Molecule Force Spectroscopy

Mechanical stability of Ca2+-responsive β-roll peptides (RTX) is largely responsible for the Ca2+-dependent mechanical properties of the RTX-based hydrogels.

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