scholarly journals Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations

2017 ◽  
Vol 13 (4) ◽  
pp. 1794-1811 ◽  
Author(s):  
Casey T. Andrews ◽  
Brady A. Campbell ◽  
Adrian H. Elcock
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Single Stranded Dna ◽  
Explicit Solvent ◽  
Dynamics Simulations

scholarly journals New CHARMM force field parameters for dehydrated amino acid residues, the key to lantibiotic molecular dynamics simulations

RSC Advances ◽  
2014 ◽  
Vol 4 (89) ◽  
pp. 48621-48631 ◽  
Author(s):  
Eleanor R. Turpin ◽  
Sam Mulholland ◽  
Andrew M. Teale ◽  
Boyan B. Bonev ◽  
Jonathan D. Hirst
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Force Field ◽  
Molecular Dynamics Simulations ◽  
Amino Acid Residues ◽  
Charmm Force Field ◽  
Force Field Parameters ◽  
Dynamics Simulations

scholarly journals A Novel Quali-Quantitative Defect of VWF

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1032-1032
Author(s):  
Tom Van De Berg ◽  
Alice Todaro ◽  
Joyce van Beers ◽  
Kanin Wichapong ◽  
Floor Heubel-Moenen ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Genetic Analysis ◽  
Molecular Dynamics Simulations ◽  
Mrna Level ◽  
Bleeding Tendency ◽  
Unknown Significance ◽  
Dynamics Simulations ◽  
Von Willebrand

Abstract Background Von Willebrand Factor (VWF) is a multimeric protein largely involved in both primary and secondary hemostasis. The diagnosis and classification of von Willebrand Disease (VWD) patients can be challenging. In this poster we explore the genetic defects and their structural consequences in a VWD patient with a disproportionately high bleeding phenotype for her VWD severity. A 31-year old female, initially diagnosed with VWD type 1, presented herself with a bleeding tendency (ISTH-BAT 13) disproportionate to the severity of her VWD with antigen levels of 36%. Additional analysis showed decreased FVIII-binding at 28%. The combination of both quantitative and functional defects of VWF was an indication for further genetic analysis in order to better define the subtype of VWD. Aims Genetic and structural analysis of VWF in a patient with a disproportionally high bleeding phenotype with regard to a mild decrease in VWF antigen. Methods Routine laboratory analysis for VWD was performed. Genetic screening was performed by exome sequencing of hemostasis related genes. VWF mRNA analysis was carried out by RT-PCR and Sanger sequencing. The X-ray structure of furin in complex with a peptide-based inhibitor (PDB ID: 6YD7) was used as a template to construct furin-VWF (759HR(R760S)SKRS764) complex. The derived structures (furin in complex with WT/R760S-VWF) were subjected to molecular dynamics (MD) simulations (200ns) and binding free energy (BFE) calculations by using standard parameters and protocols implemented in AMBER20 program. Results Routine analysis showed PFA-ADP and PFA EPI >300 seconds, VWF:ACT of 37% with a VWF:AG of 36%. Collagen binding and FVIII-binding were 46% and 28% respectively. Genetic analysis of the VWF gene disclosed 2 heterozygous variants of unknown significance (VUS): c.2771 G>A (exon 21, p.Arg924Gln) has a 1-2.5% population prevalence and has been previously described in type 1 and 2N VWD. The other VUS (c.2278 C>A; exon 17) is a novel mutation predicting a major amino acid substitution (p.Arg760Ser) in the D2-domain of VWF. Sequencing of exons 17 and 21 in the patient's VWF mRNA revealed homozygosity for the mutated allele at both mutation sites, indicating that the two variants are in cis and that the 'normal' allele is not expressed at mRNA level. Molecular dynamics simulations of the novel c.2278 C>A mutation (Arg760Ser) predicts a markedly decreased binding of furin to its VWF binding site, possibly decreasing or preventing VWF pro-peptide cleavage. This in turn has been shown to lead to reduced FVIII-binding of VWF. Conclusion Genetic analysis shows one polymorphism (c.2771 G>A) and one variation of unknown significance (c.2278 C>A) in the patient's VWF-gene. The polymorphism is known to be of low pathogenicity. The c. 2278 C>A mutation was not known in any of the mutation databases and is a novel VWF mutation. Both mutations were shown to be present on the same allele. As the wild-type allele was not expressed on mRNA level, all of the patient's VWF protein includes both amino acid substitutions. Modeling and molecular dynamics simulations show a markedly decreased affinity of furin to its cleavage site on the VWF protein due to the Arg760Ser substitution, likely resulting in a persistent pro-peptide binding to the mature VWF protein. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Using molecular dynamics simulations to identify the key factors responsible for chiral recognition by an amino acid-based molecular micelle

2018 ◽  
Vol 40 (5) ◽  
pp. 716-727 ◽  
Author(s):  
Kevin F. Morris ◽  
Eugene J. Billiot ◽  
Fereshteh H. Billiot ◽  
Jordan A. Ingle ◽  
Kevin B. Krause ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Chiral Recognition ◽  
Key Factors ◽  
Dynamics Simulations

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

Prediction of aqueous free energies of solvation using coupled QM and MM explicit solvent simulations

2020 ◽  
Vol 22 (15) ◽  
pp. 8021-8034
Author(s):  
Daniel Sadowsky ◽  
J. Samuel Arey
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Free Energies ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Ionic Solutes

A method based on molecular dynamics simulations which employ two distinct levels of theory is proposed and tested for the prediction of Gibbs free energies of solvation for non-ionic solutes in water.

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