Self-assembly of aromatic amino acids: a molecular dynamics study

2018 ◽  
Vol 20 (48) ◽  
pp. 30525-30536 ◽  
Author(s):  
Sahin Uyaver ◽  
Helen W. Hernandez ◽  
M. Gokhan Habiboglu
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Self Assembly ◽  
Aromatic Amino Acids

Common structures identified in the assembly of aromatic amino acids and their mixtures include the four-fold tube (a and b) and the zig-zag structure (c and d).

Single Amino Acid Based Self-Assemblies of Cysteine and Methionine

2018 ◽  
Author(s):  
Nidhi Gour ◽  
Bharti Koshti ◽  
Chandra Kanth P. ◽  
Dhruvi Shah ◽  
Vivek Shinh Kshatriya ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Self Assembly ◽  
Aromatic Amino Acids ◽  
Neutral Condition ◽  
Single Amino Acid ◽  
Binding Assays ◽  
Human Neuroblastoma ◽  
Cytotoxicity Assays ◽  
First Time

We report for the very first time self-assembly of Cysteine and Methionine to discrenible strucutres under neutral condition. To get insights into the structure formation, thioflavin T and Congo red binding assays were done which revealed that aggregates may not have amyloid like characteristics. The nature of interactions which lead to such self-assemblies was purported by coincubating assemblies in urea and mercaptoethanol. Further interaction of aggregates with short amyloidogenic dipeptide diphenylalanine (FF) was assessed. While cysteine aggregates completely disrupted FF fibres, methionine albeit triggered fibrillation. The cytotoxicity assays of cysteine and methionine structures were performed on Human Neuroblastoma IMR-32 cells which suggested that aggregates are not cytotoxic in nature and thus, may not have amyloid like etiology. The results presented in the manuscript are striking, since to the best of our knowledge,this is the first report which demonstrates that even non-aromatic amino acids (cysteine and methionine) can undergo spontaneous self-assembly to form ordered aggregates.

scholarly journals Allosteric Role of Substrate Occupancy Toward the Alignment of P-glycoprotein Nucleotide Binding Domains

2018 ◽  
Author(s):  
Lurong Pan ◽  
Stephen G Aller
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Lipid Bilayer ◽  
Small Molecule ◽  
Aromatic Amino Acids ◽  
Drug Binding ◽  
Atp Binding ◽  
Binding Domains ◽  
P Glycoprotein ◽  
Binding Cavity

AbstractP-glycoprotein (Pgp) is an ATP-binding cassette transporter that eliminates toxins from the cell but causes multidrug resistance in chemotherapies. The crystal structures of Pgp revealed drug-like compounds bound to an inward-facing conformation in which the energy-harnessing nucleotide binding domains (NBDs) were widely separated with no interfacial interaction. Following drug binding, inward-facing Pgp must transition to an NBD dimer conformation to achieve ATP binding and hydrolysis at canonical sites defined by both halves of the interface. However, given the high degree of flexibility shown for this transporter, it is difficult to envision how NBDs overcome entropic considerations for achieving proper alignment in order to form the canonical ATP binding site. We explored the hypothesis that substrate occupancy of the polyspecific drug-binding cavity plays a role in the proper alignment of NBDs using computational approaches. We conducted twelve atomistic molecular dynamics (MD) simulations (100-300 ns) on inward-facing Pgp in a lipid bilayer with and without small molecule substrates to ascertain effects of drug occupancy on NBD dimerization. Both apo- and drug-occupied simulations showed NBDs approaching each other compared to the crystal structures. Apo-Pgp reached a pseudo-dimerization in which NBD signature motifs for ATP binding exhibited a significant misalignment during closure. In contrast, occupancy of three established substrates positioned by molecular docking achieved NBD alignment that was much more compatible with a canonical NBD dimerization trajectory. Additionally, aromatic amino acids, known to confer the polyspecific drug-binding characteristic of the internal pocket, may also govern polyspecific drug access to the cavity. The enrichment of aromatics comprising the TM4-TM6 portal suggested a preferential pathway over the aromatic-poor TM10-TM12 for lateral drug entry from the lipid bilayer. Our study also suggested that drug polyspecificity is enhanced due to a synergism between multiple drug-domain interactions involving 36 residues identified in TM1, 5, 6, 7, 11 and 12.Author SummaryP-glycoprotein (Pgp) is an active drug pump known to cause clinical multi-drug resistance. The static atomic structure of Pgp was determined by trapping an inward-facing conformation bound to small molecule substrates by crystallization, however the effect of substrates on Pgp dynamics following binding is poorly understood. In this study, six apo-Pgp and six drug-occupied Pgp were simulated using unconstrained atomistic molecular dynamics (MD) for 100-300 ns. We demonstrate an allosteric communication of drug binding “from the top down”, that is from the TMDs to the NBDs that promotes NBD alignment and trajectories that favor canonical ATP binding. Other analyses suggested that aromatic amino acids in both the central drug-binding cavity and the “front portal” (TM4/TM6) confer polyspecific recognition. Additionally, comparison of the thermal B-factors between the experimental measurement and MD simulation indicated that different physical and chemical environments (temperature, in surfo vs. in meso, solution compositions) only alter the regional scales of thermal fluctuations but not the patterns of these motions. Lastly, DCCM and normal mode analyses were used to decipher thermal motions and the motion correlations between various domains in Pgp, allowing us to propose a substrate allosteric mechanism and an energy conservation mechanism during the catalytic cycle.

Self-Assembly Evolution of N-Terminal Aromatic Amino Acids with Transient Supramolecular Chirality

2020 ◽  
Vol 11 (4) ◽  
pp. 1490-1496 ◽  
Author(s):  
Shixin Xue ◽  
Nan Zhang ◽  
Xiaoling Hu ◽  
Yongfei Zeng ◽  
Jingbo Zhang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Self Assembly ◽  
Aromatic Amino Acids ◽  
Supramolecular Chirality

scholarly journals Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

2021 ◽  
Vol 22 (16) ◽  
pp. 8861
Author(s):  
Angela Corvino ◽  
Ida Cerqua ◽  
Alessandra Lo Bianco ◽  
Giuseppe Caliendo ◽  
Ferdinando Fiorino ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Dynamics ◽  
Amino Acids ◽  
Aromatic Amino Acids ◽  
Sphingolipid Metabolism ◽  
Vascular Relaxation ◽  
Muscle Fibrosis ◽  
Cell Penetrating ◽  
Dynamics Simulations ◽  
Skeletal Muscle Fibrosis

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.

scholarly journals Controlled self-assembly of modified aromatic amino acids

2021 ◽  
Author(s):  
Nidhi Gour ◽  
Vivekshinh Kshtriya ◽  
Bharti Koshti ◽  
Hanuman Narode ◽  
Soumick Naskar
Keyword(s):  
Amino Acids ◽  
Self Assembly ◽  
Aromatic Amino Acids

Single Amino Acid Based Self-Assemblies of Cysteine and Methionine

2018 ◽  
Author(s):  
Nidhi Gour ◽  
Bharti Koshti ◽  
Chandra Kanth P. ◽  
Dhruvi Shah ◽  
Vivek Shinh Kshatriya ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Self Assembly ◽  
Aromatic Amino Acids ◽  
Neutral Condition ◽  
Single Amino Acid ◽  
Binding Assays ◽  
Human Neuroblastoma ◽  
Cytotoxicity Assays ◽  
First Time

We report for the very first time self-assembly of Cysteine and Methionine to discrenible strucutres under neutral condition. To get insights into the structure formation, thioflavin T and Congo red binding assays were done which revealed that aggregates may not have amyloid like characteristics. The nature of interactions which lead to such self-assemblies was purported by coincubating assemblies in urea and mercaptoethanol. Further interaction of aggregates with short amyloidogenic dipeptide diphenylalanine (FF) was assessed. While cysteine aggregates completely disrupted FF fibres, methionine albeit triggered fibrillation. The cytotoxicity assays of cysteine and methionine structures were performed on Human Neuroblastoma IMR-32 cells which suggested that aggregates are not cytotoxic in nature and thus, may not have amyloid like etiology. The results presented in the manuscript are striking, since to the best of our knowledge,this is the first report which demonstrates that even non-aromatic amino acids (cysteine and methionine) can undergo spontaneous self-assembly to form ordered aggregates.

Self-Assembling l-d-l-Tripeptides Dance the Twist

Synlett ◽  
2020 ◽  
Vol 31 (05) ◽  
pp. 434-438 ◽  
Author(s):  
Maria C. Cringoli ◽  
Ottavia Bellotto ◽  
Rita De Zorzi ◽  
Attilio V. Vargiu ◽  
Silvia Marchesan
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Single Crystal ◽  
Self Assembly ◽  
Building Blocks ◽  
Supramolecular Structures ◽  
X Ray Diffraction ◽  
Supramolecular Materials ◽  
X Ray ◽  
Self Assembling

Minimalistic peptides composed of d- and l-amino acids are attractive building blocks for functional supramolecular materials, including catalysts. d-Amino acids have long been known to promote turn conformations in peptides, yet unexpected twists continue to emerge on their effects on self-assembly. The combination of single-crystal X-ray diffraction and full-atom molecular dynamics have finally unraveled fine details of how l-d-l-tripeptides visit different conformations in solution and establish key interactions in supramolecular structures.

scholarly journals Single Amino Acid Based Self-Assemblies of Cysteine and Methionine

2018 ◽  
Author(s):  
Nidhi Gour ◽  
Bharti Koshti ◽  
Chandra Kanth P. ◽  
Dhruvi Shah ◽  
Vivek Shinh Kshatriya ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Self Assembly ◽  
Aromatic Amino Acids ◽  
Neutral Condition ◽  
Single Amino Acid ◽  
First Report ◽  
First Time

We report for the very first time self-assembly of Cysteine and Methionine to discrenible strucutres under neutral condition. The nature of interactions which lead to such self-assemblies was purported by coincubating assemblies in urea and mercaptoethanol. Further interaction of aggregates with short amyloidogenic dipeptide diphenylalanine (FF) was assessed. While cysteine aggregates completely disrupted FF fibres, methionine albeit triggered fibrillation. . The results presented in the manuscript are striking, since to the best of our knowledge,this is the first report which demonstrates that even non-aromatic amino acids (cysteine and methionine) can undergo spontaneous self-assembly to form ordered aggregates.

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