Conformational Changes of the Wild-Type hIAPP and the S20P Mutant in Water Revealed by Molecular Dynamics Simulations

2011 ◽  
Vol 396-398 ◽  
pp. 1554-1557
Author(s):  
Mian Wang ◽  
Jian Yi Wang
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Conformational Changes ◽  
Amyloid Fibrils ◽  
Helical Structure ◽  
Wild Type ◽  
Hydrogen Bond Interaction ◽  
Hydrogen Bond Networks ◽  
Α Helix ◽  
Dynamics Simulations

Conformational changes of wild-type (WT) hIAPP and the S20P mutant in explicit water are investigated using molecular dynamics. In the whole simulation, WT shows compacter structure and has more hydrogen-bond networks than S20P. The residues 14-18 in WT is always maintained as a helical structure which is stabilized by the hydrogen bond between Ser20 and NH group of His18, and the other regions in WT partially loosen from α-helix structures into the coil structures. The S20P mutant in a shortage of hydrogen-bond interaction unfolds faster than WT. This work provides insight into the specific conformation of IAPP which is associated with the generation of amyloid fibrils.

scholarly journals The rupture mechanism of rubredoxin is more complex than previously thought

2020 ◽  
Vol 11 (23) ◽  
pp. 6036-6044
Author(s):  
Maximilian Scheurer ◽  
Andreas Dreuw ◽  
Martin Head-Gordon ◽  
Tim Stauch
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Molecular Dynamics Simulations ◽  
Strain Analysis ◽  
Rupture Force ◽  
Iron Sulfur ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Rupture Mechanism ◽  
Sulfur Bond

Using steered molecular dynamics simulations and strain analysis it is shown that, in contrast to previous assumptions, the experimentally found low rupture force of the iron–sulfur-bond in rubredoxin cannot be explained by hydrogen bond networks.

Molecular dynamics simulations of N-methylacetamide (NMA) in water by the ABEEM/MM model

2009 ◽  
Vol 87 (12) ◽  
pp. 1738-1746 ◽  
Author(s):  
Ping Qian ◽  
Li-Nan Lu ◽  
Zhong-Zhi Yang
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Potential Model ◽  
Lone Pair ◽  
Static Properties ◽  
Range Interaction ◽  
Hydrogen Bond Interaction ◽  
Lone Pair Electron ◽  
Dynamics Simulations

The N-methylacetamide (NMA) is a very interesting kind of compound and often serves as a model of the peptide bond. The interaction between NMA and water provides a convenient prototype for the solvation of peptides in aqueous solutions. We have carried out molecular dynamics (MD) simulations of a NMA molecule in water under 1 atm and 298 K. The simulations make use of the newly developed NMA–water fluctuating charge ABEEM/MM potential model ( Yang, Z. Z.; Qian, P. J. Chem. Phys. 2006, 125, 064311 ), which is based on the combination of the atom-bond electronegativity equalization method (ABEEM) and molecular mechanics (MM). This model has been successfully applied to NMA–water gas clusters, NMA(H2O)n (n = 1–6), and accurately reproduced many static properties. For the NMA–water ABEEM/MM potential model, two characters must be emphasized in the simulations. Firstly, the model allows the charges in system to fluctuate, responding to the ambient environment. Secondly, for two major types of intermolecular hydrogen bonds, which are the hydrogen bond forming between the lone-pair electron on amide oxygen and the water hydrogen, and the one forming between the lone-pair electron on water oxygen and the amide hydrogen, we take special treatments in describing the electrostatic interaction by the use of the parameters klpO=,H and klpO–,HN–, respectively, which explicitly describe the short-range interaction of hydrogen bonds in the hydrogen bond interaction region. All sorts of properties have been studied in detail, such as, radial distribution function, energy distribution, ABEEM charge distribution and dipole moment, and so on. These simulation results show that the ABEEM/MM-based NMA–water potential model appears to be robust, giving the solution properties in excellent agreement with other dynamics simulations on similar systems.

scholarly journals Molecular Dynamics Simulations Suggest a Non-Doublet Decoding Model of –1 Frameshifting by tRNASer3

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 745 ◽  
Author(s):  
Caulfield ◽  
Coban ◽  
Tek ◽  
Flores
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Molecular Dynamics Simulations ◽  
Wild Type ◽  
E Coli ◽  
The Third ◽  
Dynamics Simulations

In-frame decoding in the ribosome occurs through canonical or wobble Watson–Crick pairing of three mRNA codon bases (a triplet) with a triplet of anticodon bases in tRNA. Departures from the triplet–triplet interaction can result in frameshifting, meaning downstream mRNA codons are then read in a different register. There are many mechanisms to induce frameshifting, and most are insufficiently understood. One previously proposed mechanism is doublet decoding, in which only codon bases 1 and 2 are read by anticodon bases 34 and 35, which would lead to –1 frameshifting. In E. coli, tRNASer3GCU can induce –1 frameshifting at alanine (GCA) codons. The logic of the doublet decoding model is that the Ala codon’s GC could pair with the tRNASer3′s GC, leaving the third anticodon residue U36 making no interactions with mRNA. Under that model, a U36C mutation would still induce –1 frameshifting, but experiments refute this. We perform all-atom simulations of wild-type tRNASer3, as well as a U36C mutant. Our simulations revealed a hydrogen bond between U36 of the anticodon and G1 of the codon. The U36C mutant cannot make this interaction, as it lacks the hydrogen-bond-donating H3. The simulation thus suggests a novel, non-doublet decoding mechanism for −1 frameshifting by tRNASer3 at Ala codons.

Molecular dynamics simulations of wild type and mutants of botulinum neurotoxin A complexed with synaptic vesicle protein 2C

2015 ◽  
Vol 11 (1) ◽  
pp. 223-231 ◽  
Author(s):  
Feng Wang ◽  
Hua Wan ◽  
Jian-ping Hu ◽  
Shan Chang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Synaptic Vesicle ◽  
Conformational Changes ◽  
Botulinum Neurotoxin ◽  
Wild Type ◽  
Botulinum Neurotoxin A ◽  
Synaptic Vesicle Protein ◽  
Dynamics Simulations ◽  
The Relationship

Using molecular dynamics simulations, we investigate the relationship between the conformational changes of BoNT/A-RBD:SV2C-LD and the interfacial interactions.

Molecular Dynamics Simulations of Water, Silica, and Aqueous Mixtures in Bulk and Confinement

2018 ◽  
Vol 232 (7-8) ◽  
pp. 1187-1225 ◽  
Author(s):  
Julian Geske ◽  
Michael Harrach ◽  
Lotta Heckmann ◽  
Robin Horstmann ◽  
Felix Klameth ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Molecular Dynamics Simulations ◽  
Aqueous Mixtures ◽  
Simulation Data ◽  
Hydrogen Bond Networks ◽  
Simulation Results ◽  
Dynamics Simulations ◽  
Anomalies Of Water

Abstract Aqueous systems are omnipresent in nature and technology. They show complex behaviors, which often originate in the existence of hydrogen-bond networks. Prominent examples are the anomalies of water and the non-ideal behaviors of aqueous solutions. The phenomenology becomes even richer when aqueous liquids are subject to confinement. To this day, many properties of water and its mixtures, in particular, under confinement, are not understood. In recent years, molecular dynamics simulations developed into a powerful tool to improve our knowledge in this field. Here, our simulation results for water and aqueous mixtures in the bulk and in various confinements are reviewed and some new simulation data are added to improve our knowledge about the role of interfaces. Moreover, findings for water are compared with results for silica, exploiting that both systems form tetrahedral networks.

scholarly journals Exploring the Early Stages of the Amyloid Aβ(1–42) Peptide Aggregation Process: An NMR Study

2021 ◽  
Vol 14 (8) ◽  
pp. 732
Author(s):  
Angelo Santoro ◽  
Manuela Grimaldi ◽  
Michela Buonocore ◽  
Ilaria Stillitano ◽  
Anna Maria D’Ursi
Keyword(s):  
Conformational Changes ◽  
Amyloid Fibrils ◽  
Structural Model ◽  
Conformational Transition ◽  
Helical Structure ◽  
Aggregation Process ◽  
Nmr Study ◽  
Aβ Aggregation ◽  
Dynamics Simulations ◽  
Β Sheet

Alzheimer’s disease (AD) is a neurodegenerative pathology characterized by the presence of neurofibrillary tangles and amyloid plaques, the latter mainly composed of Aβ(1–40) and Aβ(1–42) peptides. The control of the Aβ aggregation process as a therapeutic strategy for AD has prompted the interest to investigate the conformation of the Aβ peptides, taking advantage of computational and experimental techniques. Mixtures composed of systematically different proportions of HFIP and water have been used to monitor, by NMR, the conformational transition of the Aβ(1–42) from soluble α-helical structure to β-sheet aggregates. In the previous studies, 50/50 HFIP/water proportion emerged as the solution condition where the first evident Aβ(1–42) conformational changes occur. In the hypothesis that this solvent reproduces the best condition to catch transitional helical-β-sheet Aβ(1–42) conformations, in this study, we report an extensive NMR conformational analysis of Aβ(1–42) in 50/50 HFIP/water v/v. Aβ(1–42) structure was solved by us, giving evidence that the evolution of Aβ(1–42) peptide from helical to the β-sheet may follow unexpected routes. Molecular dynamics simulations confirm that the structural model we calculated represents a starting condition for amyloid fibrils formation.

scholarly journals The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoqian Zhang ◽  
Hua Yu ◽  
Xiangdong Liu ◽  
Chen Song
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Calcium Release ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Wild Type ◽  
Hydrophobic Region ◽  
In The Wild ◽  
Dynamics Simulations ◽  
The Impact

The calcium release-activated calcium channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the wild-type. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously unobserved feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.

scholarly journals Molecular Dynamics Simulations Study of the Interactions between Human Dipeptidyl-Peptidase III and Two Substrates

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6492
Author(s):  
Shitao Zhang ◽  
Shuai Lv ◽  
Xueqi Fu ◽  
Lu Han ◽  
Weiwei Han ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Biological Activities ◽  
Catalytic Efficiency ◽  
Dipeptidyl Peptidase ◽  
Pain Modulation ◽  
Ang Ii ◽  
Α Helix ◽  
Dynamics Simulations

Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. In this study, 500 ns molecular dynamics simulations were performed on free-hDPP III (PDB code: 5E33), hDPP III–Ang II (PDB code: 5E2Q), and hDPP III–IVYPW (PDB code: 5E3C) to explore how these two peptides affect the catalytic efficiency of enzymes in terms of the binding mode and the conformational changes. Our results indicate that in the case of the hDPP III–Ang II complex, subsite S1 became small and hydrophobic, which might be propitious for the nucleophile to attack the substrate. The structures of the most stable conformations of the three systems revealed that Arg421-Lys423 could form an α-helix with the presence of Ang II, but only part of the α-helix was produced in hDPP III-IVYPW. As the hinge structure in hDPP III, the conformational changes that took place in the Arg421-Lys423 residue could lead to the changes in the shape and space of the catalytic subsites, which might allow water to function as a nucleophile to attack the substrate. Our results may provide new clues to enable the design of new inhibitors for hDPP III in the future.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

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