scholarly journals Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 337 ◽  
Author(s):  
Hognon ◽  
Gebus ◽  
Barone ◽  
Monari
Keyword(s):  
Electrostatic Interactions ◽  
Empty Site ◽  
Quadruplex Structure ◽  
Abasic Sites ◽  
Human Dna ◽  
Guanine Quadruplex ◽  
Guanine Base ◽  
The Stability ◽  
Dynamics Simulations

By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.

The Role of Hydrophobicity in the Stability and pH-Switchability of (RXDX)4 and Coumarin-RXDX Conjugate β-Sheets

2020 ◽  
Author(s):  
Ryan Weber ◽  
Martin McCullagh
Keyword(s):  
Biological Imaging ◽  
Ph Sensing ◽  
Hydrophobic Residue ◽  
Ideal Candidate ◽  
Self Assembling ◽  
Sensing Applications ◽  
Β Sheets ◽  
The Stability ◽  
Dynamics Simulations

<p>pH-switchable, self-assembling materials are of interest in biological imaging and sensing applications. Here we propose that combining the pH-switchability of RXDX (X=Ala, Val, Leu, Ile, Phe) peptides and the optical properties of coumarin creates an ideal candidate for these materials. This suggestion is tested with a thorough set of all-atom molecular dynamics simulations. We first investigate the dependence of pH-switchabiliy on the identity of the hydrophobic residue, X, in the bare (RXDX)<sub>4</sub> systems. Increasing the hydrophobicity stabilizes the fiber which, in turn, reduces the pH-switchabilty of the system. This behavior is found to be somewhat transferable to systems in which a single hydrophobic residue is replaced with a coumarin containing amino acid. In this case, conjugates with X=Ala are found to be unstable and both pHs while conjugates with X=Val, Leu, Ile and Phe are found to form stable β-sheets at least at neutral pH. The (RFDF)<sub>4</sub>-coumarin conjugate is found to have the largest relative entropy value of 0.884 +/- 0.001 between neutral and acidic coumarin ordering distributions. Thus, we posit that coumarin-(RFDF)<sub>4</sub> containing peptide sequences are ideal candidates for pH-sensing bioelectronic materials.</p>

scholarly journals Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

2021 ◽  
Vol 22 (5) ◽  
pp. 2732
Author(s):  
Nadine Reichhart ◽  
Vladimir M. Milenkovic ◽  
Christian H. Wetzel ◽  
Olaf Strauß
Keyword(s):  
Transmembrane Protein ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Functional Consequences ◽  
New Perspective ◽  
The Stability ◽  
Dynamics Simulations ◽  
And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

scholarly journals Tubulin tails and their modifications regulate protein diffusion on microtubules

2020 ◽  
Vol 117 (16) ◽  
pp. 8876-8883 ◽  
Author(s):  
Lavi S. Bigman ◽  
Yaakov Levy
Keyword(s):  
Molecular Mechanism ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Coarse Grained ◽  
Protein Diffusion ◽  
Intrinsically Disordered ◽  
Essential Components ◽  
Regulate Protein ◽  
Dynamics Simulations

Microtubules (MTs) are essential components of the eukaryotic cytoskeleton that serve as “highways” for intracellular trafficking. In addition to the well-known active transport of cargo by motor proteins, many MT-binding proteins seem to adopt diffusional motility as a transportation mechanism. However, because of the limited spatial resolution of current experimental techniques, the detailed mechanism of protein diffusion has not been elucidated. In particular, the precise role of tubulin tails and tail modifications in the diffusion process is unclear. Here, using coarse-grained molecular dynamics simulations validated against atomistic simulations, we explore the molecular mechanism of protein diffusion along MTs. We found that electrostatic interactions play a central role in protein diffusion; the disordered tubulin tails enhance affinity but slow down diffusion, and diffusion occurs in discrete steps. While diffusion along wild-type MT is performed in steps of dimeric tubulin, the removal of the tails results in a step of monomeric tubulin. We found that the energy barrier for diffusion is larger when diffusion on MTs is mediated primarily by the MT tails rather than the MT body. In addition, globular proteins (EB1 and PRC1) diffuse more slowly than an intrinsically disordered protein (Tau) on MTs. Finally, we found that polyglutamylation and polyglycylation of tubulin tails lead to slower protein diffusion along MTs, although polyglycylation leads to faster diffusion across MT protofilaments. Taken together, our results explain experimentally observed data and shed light on the roles played by disordered tubulin tails and tail modifications in the molecular mechanism of protein diffusion along MTs.

scholarly journals Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1104
Author(s):  
Rafal Madaj ◽  
Bartlomiej Gostynski ◽  
Roza Pawlowska ◽  
Arkadiusz Chworos
Keyword(s):  
Molecular Dynamics ◽  
Alkaline Phosphatase ◽  
Electrostatic Interactions ◽  
Thermodynamic Integration ◽  
Ligand Docking ◽  
In Silico Studies ◽  
Tissue Nonspecific Alkaline Phosphatase ◽  
The Stability ◽  
Dynamics Simulations ◽  
Hydrolysis Of

Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of β,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties.

The Role of Hydrophobicity in the Stability and pH-Switchability of (RXDX)4 and Coumarin-RXDX Conjugate β-Sheets

2020 ◽  
Author(s):  
Ryan Weber ◽  
Martin McCullagh
Keyword(s):  
Biological Imaging ◽  
Ph Sensing ◽  
Hydrophobic Residue ◽  
Ideal Candidate ◽  
Self Assembling ◽  
Sensing Applications ◽  
Β Sheets ◽  
The Stability ◽  
Dynamics Simulations

<p>pH-switchable, self-assembling materials are of interest in biological imaging and sensing applications. Here we propose that combining the pH-switchability of RXDX (X=Ala, Val, Leu, Ile, Phe) peptides and the optical properties of coumarin creates an ideal candidate for these materials. This suggestion is tested with a thorough set of all-atom molecular dynamics simulations. We first investigate the dependence of pH-switchabiliy on the identity of the hydrophobic residue, X, in the bare (RXDX)<sub>4</sub> systems. Increasing the hydrophobicity stabilizes the fiber which, in turn, reduces the pH-switchabilty of the system. This behavior is found to be somewhat transferable to systems in which a single hydrophobic residue is replaced with a coumarin containing amino acid. In this case, conjugates with X=Ala are found to be unstable and both pHs while conjugates with X=Val, Leu, Ile and Phe are found to form stable β-sheets at least at neutral pH. The (RFDF)<sub>4</sub>-coumarin conjugate is found to have the largest relative entropy value of 0.884 +/- 0.001 between neutral and acidic coumarin ordering distributions. Thus, we posit that coumarin-(RFDF)<sub>4</sub> containing peptide sequences are ideal candidates for pH-sensing bioelectronic materials.</p>

scholarly journals The role of Lys525 on the head-group anchoring of fatty acids in the highest affinity binding site of albumin

2010 ◽  
Vol 24 (1-2) ◽  
pp. 159-163 ◽  
Author(s):  
Bruno Rizzuti ◽  
Manuela Pantusa ◽  
Rita Guzzi
Keyword(s):  
Fatty Acids ◽  
Electrostatic Interactions ◽  
Spectroscopic Properties ◽  
Terminal Group ◽  
Head Group ◽  
Affinity Binding ◽  
Long Chain Fatty Acids ◽  
Lipid Chain ◽  
Dynamics Simulations

Human serum albumin provides the transport of long-chain fatty acids in the blood through three high-affinity and four low-affinity binding sites. Molecular dynamics simulations have been performed to investigate the anchoring of palmitic acid molecules to the protein. In the site with the highest affinity, Site 5, the key residue Lys525 not only binds the head-group of the palmitate ion by electrostatic interactions with its charged terminal group, but it also accommodates the first portion of the lipid chain by non-electrostatic interactions with the rest of its sidechain. The flexibility of Lys525, and in particular of the dihedral angleχ3, is suggested to account for a number of spectroscopic properties observed in correspondence with the entrance of the hydrophobic pocket constituting Site 5.

Stability of wall bounded, shear flows of dense granular materials: the role of the Couette gap, the wall velocity and the initial concentration

2016 ◽  
Vol 791 ◽  
pp. 384-413 ◽  
Author(s):  
C. Varsakelis ◽  
M. V. Papalexandris
Keyword(s):  
Granular Material ◽  
Mechanical Model ◽  
Particle Migration ◽  
Shear Stresses ◽  
Initial Concentration ◽  
Wall Velocity ◽  
Mode Stability ◽  
The Stability ◽  
Dynamics Simulations

In this paper, the stability of a plane, unidirectional Couette flow of a dense granular material is investigated via the means of a normal mode stability analysis. Our studies are based on a continuum mechanical model for the flows of interest coupled with the constitutive expressions for the normal and the shear stresses of the granular material induced by the ${\it\mu}(I)$-rheology. According to our analysis, both the Couette gap and the wall velocity play a destabilizing role in the flows of interest as opposed to the initial concentration that acts as stabilizer. For sufficiently high Couette gaps and wall velocities, unstable modes are recovered. The predicted instability manifests itself through shear-induced dilatancy that, in turn, engenders particle migration and the formation of bulbs, similar to the ones that have been acquired through molecular dynamics simulations.

scholarly journals D-Retro Inverso (DRI) Amylin and the Stability of Amylin Fibrils

2020 ◽  
Author(s):  
Preeti Pandey ◽  
Natalie Nguyen ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Type Ii Diabetes ◽  
Type Ii ◽  
Fibril Structure ◽  
Elongation Process ◽  
The Stability ◽  
Dynamics Simulations ◽  
Potential Use

AbstractMotivated by the role that amylin aggregates pay in type-II diabetes, we compare the stability of regular amylin fibrils with the stability of fibrils where L-amino acid chains are replaced by D-Retro Inverso (DRI) amylin, i.e., peptides where the sequence of amino acids is reversed, and at the same time the L-amino acids are replaced by their mirror images. Our molecular dynamics simulations show that despite leading to only marginal difference in fibril structure and stability, aggregating DRI-amylin peptides have different pattern of contacts and hydrogen bonding. Because of these differences does DRI-amylin, when interacting with regular (L) amylin, alter the elongation process and lowers the stability of hybrid amylin fibrils. Our results suggest not only a potential use of DRI-amylin as inhibitor of amylin fibril-formation, but points also to the possibility of using insertion of DRI-proteins in L-assemblies as a way to probe the role of certain kinds of hydrogen bonds in supra-molecular assemblies or aggregates.

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