scholarly journals An unusual amino acid substitution within hummingbird cytochrome c oxidase alters a key proton-conducting channel

2019 ◽  
Author(s):  
Cory D. Dunn ◽  
Bala Anı Akpınar ◽  
Vivek Sharma
Keyword(s):  
Amino Acid ◽  
Life Histories ◽  
Amino Acid Position ◽  
Proton Channel ◽  
Conducting Channel ◽  
Specific Manner ◽  
Dynamics Simulations ◽  
A Site ◽  
Unique Amino Acid ◽  
Unusual Amino Acid

ABSTRACTHummingbirds in flight exhibit the highest metabolic rate of all vertebrates. The bioenergetic requirements associated with sustained hovering flight raise the possibility of unique amino acid substitutions that would enhance aerobic metabolism. Here, we have identified a non-conservative substitution within the mitochondria-encoded cytochrome c oxidase subunit I (COI) that is fixed within hummingbirds, but not among other vertebrates. This unusual change is also rare among metazoans, but can be identified in several clades with diverse life histories. We performed atomistic molecular dynamics simulations using bovine and hummingbird COI models, thereby bypassing experimental limitations imposed by the inability to modify mtDNA in a site-specific manner. Intriguingly, our findings suggest that COI amino acid position 153 (bovine numbering system) provides control over the hydration and activity of a key proton channel in COX. We discuss potential phenotypic outcomes linked to this alteration encoded by the hummingbird mitochondrial genome.

scholarly journals An Unusual Amino Acid Substitution Within Hummingbird Cytochrome c Oxidase Alters a Key Proton-Conducting Channel

2020 ◽  
Vol 10 (7) ◽  
pp. 2477-2485 ◽  
Author(s):  
Cory D. Dunn ◽  
Bala Anı Akpınar ◽  
Vivek Sharma
Keyword(s):  
Amino Acid ◽  
Life Histories ◽  
Amino Acid Position ◽  
Proton Channel ◽  
Mitochondrial Genomes ◽  
Specific Manner ◽  
Dynamics Simulations ◽  
A Site ◽  
Unique Amino Acid ◽  
Unusual Amino Acid

Hummingbirds in flight exhibit the highest mass-specific metabolic rate of all vertebrates. The bioenergetic requirements associated with sustained hovering flight raise the possibility of unique amino acid substitutions that would enhance aerobic metabolism. Here, we have identified a non-conservative substitution within the mitochondria-encoded cytochrome c oxidase subunit I (COI) that is fixed within hummingbirds, but not among other vertebrates. This unusual change is also rare among metazoans, but can be identified in several clades with diverse life histories. We performed atomistic molecular dynamics simulations using bovine and hummingbird COI models, thereby bypassing experimental limitations imposed by the inability to modify mtDNA in a site-specific manner. Intriguingly, our findings suggest that COI amino acid position 153 (bovine numbering convention) provides control over the hydration and activity of a key proton channel in COX. We discuss potential phenotypic outcomes linked to this alteration encoded by hummingbird mitochondrial genomes.

scholarly journals Variants of β-Lactamase KPC-2 That Are Resistant to Inhibition by Avibactam

2015 ◽  
Vol 59 (7) ◽  
pp. 3710-3717 ◽  
Author(s):  
Krisztina M. Papp-Wallace ◽  
Marisa L. Winkler ◽  
Magdalena A. Taracila ◽  
Robert A. Bonomo
Keyword(s):  
Amino Acid ◽  
Molecular Modeling ◽  
Clavulanic Acid ◽  
Amino Acid Position ◽  
Proton Donor ◽  
Single Amino Acid ◽  
Wild Type ◽  
Content Type ◽  
Mechanistic Basis ◽  
Dynamics Simulations

ABSTRACTKPC-2 is the most prevalent class A carbapenemase in the world. Previously, KPC-2 was shown to hydrolyze the β-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam. In addition, substitutions at amino acid position R220 in the KPC-2 β-lactamase increased resistance to clavulanic acid. A novel bridged diazabicyclooctane (DBO) non-β-lactam β-lactamase inhibitor, avibactam, was shown to inactivate the KPC-2 β-lactamase. To better understand the mechanistic basis for inhibition of KPC-2 by avibactam, we tested the potency of ampicillin-avibactam and ceftazidime-avibactam against engineered variants of the KPC-2 β-lactamase that possessed single amino acid substitutions at important sites (i.e., Ambler positions 69, 130, 234, 220, and 276) that were previously shown to confer inhibitor resistance in TEM and SHV β-lactamases. To this end, we performed susceptibility testing, biochemical assays, and molecular modeling.Escherichia coliDH10B carrying KPC-2 β-lactamase variants with the substitutions S130G, K234R, and R220M demonstrated elevated MICs for only the ampicillin-avibactam combinations (e.g., 512, 64, and 32 mg/liter, respectively, versus the MICs for wild-type KPC-2 at 2 to 8 mg/liter). Steady-state kinetics revealed that the S130G variant of KPC-2 resisted inactivation by avibactam; thek2/Kratio was significantly lowered 4 logs for the S130G variant from the ratio for the wild-type enzyme (21,580 M−1s−1to 1.2 M−1s−1). Molecular modeling and molecular dynamics simulations suggested that the mobility of K73 and its ability to activate S70 (i.e., function as a general base) may be impaired in the S130G variant of KPC-2, thereby explaining the slowed acylation. Moreover, we also advance the idea that the protonation of the sulfate nitrogen of avibactam may be slowed in the S130G variant, as S130 is the likely proton donor and another residue, possibly K234, must compensate. Our findings show that residues S130 as well as K234 and R220 contribute significantly to the mechanism of avibactam inactivation of KPC-2. Fortunately, the emergence of S130G, K234R, and R220M variants of KPC in the clinic should not result in failure of ceftazidime-avibactam, as the ceftazidime partner is potent againstE. coliDH10B strains possessing all of these variants.

A Novel Amino Acid Sequence-based Computational Approach to Predicting Cell-penetrating Peptides

2019 ◽  
Vol 15 (3) ◽  
pp. 206-211 ◽  
Author(s):  
Jihui Tang ◽  
Jie Ning ◽  
Xiaoyan Liu ◽  
Baoming Wu ◽  
Rongfeng Hu
Keyword(s):  
Machine Learning ◽  
Amino Acid ◽  
Amino Acid Position ◽  
Cell Penetrating Peptides ◽  
Support Vector ◽  
Cell Penetration ◽  
Drug Candidates ◽  
Machine Learning Model ◽  
Cell Penetrating ◽  
Novel Method

<P>Introduction: Machine Learning is a useful tool for the prediction of cell-penetration compounds as drug candidates. </P><P> Materials and Methods: In this study, we developed a novel method for predicting Cell-Penetrating Peptides (CPPs) membrane penetrating capability. For this, we used orthogonal encoding to encode amino acid and each amino acid position as one variable. Then a software of IBM spss modeler and a dataset including 533 CPPs, were used for model screening. </P><P> Results: The results indicated that the machine learning model of Support Vector Machine (SVM) was suitable for predicting membrane penetrating capability. For improvement, the three CPPs with the most longer lengths were used to predict CPPs. The penetration capability can be predicted with an accuracy of close to 95%. </P><P> Conclusion: All the results indicated that by using amino acid position as a variable can be a perspective method for predicting CPPs membrane penetrating capability.</P>

Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

2020 ◽  
Vol 16 (4) ◽  
pp. 451-459 ◽  
Author(s):  
Fortunatus C. Ezebuo ◽  
Ikemefuna C. Uzochukwu
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Binding Energy ◽  
Binding Site ◽  
Conformational Dynamics ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Conformational Selection ◽  
Hybrid Mechanism ◽  
Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

scholarly journals Drosophila kinesin motor domain extending to amino acid position 392 is dimeric when expressed in Escherichia coli.

1994 ◽  
Vol 269 (51) ◽  
pp. 32708
Author(s):  
T G Huang ◽  
J Suhan ◽  
D D Hackney
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Amino Acid Position ◽  
Motor Domain ◽  
Kinesin Motor

scholarly journals Electrical Breakdown Mechanism of Transformer Oil with Water Impurity: Molecular Dynamics Simulations and First-Principles Calculations

Crystals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 123
Author(s):  
Bin Cao ◽  
Ji-Wei Dong ◽  
Ming-He Chi
Keyword(s):  
Molecular Dynamics ◽  
Thermal Diffusion ◽  
First Principles ◽  
Electrical Breakdown ◽  
Transformer Oil ◽  
Water Molecules ◽  
Conducting Channel ◽  
Breakdown Mechanism ◽  
Water Impurity ◽  
Dynamics Simulations

Water impurity is the essential factor of reducing the insulation performance of transformer oil, which directly determines the operating safety and life of a transformer. Molecular dynamics simulations and first-principles electronic-structure calculations are employed to study the diffusion behavior of water molecules and the electrical breakdown mechanism of transformer oil containing water impurities. The molecular dynamics of an oil-water micro-system model demonstrates that the increase of aging acid concentration will exponentially expedite thermal diffusion of water molecules. Density of states (DOS) for a local region model of transformer oil containing water molecules indicates that water molecules can introduce unoccupied localized electron-states with energy levels close to the conduction band minimum of transformer oil, which makes water molecules capable of capturing electrons and transforming them into water ions during thermal diffusion. Subsequently, under a high electric field, water ions collide and impact on oil molecules to break the molecular chain of transformer oil, engendering carbonized components that introduce a conduction electronic-band in the band-gap of oil molecules as a manifestation of forming a conductive region in transformer oil. The conduction channel composed of carbonized components will be eventually formed, connecting two electrodes, with the carbonized components developing rapidly under the impact of water ions, based on which a large number of electron carriers will be produced similar to “avalanche” discharge, leading to an electrical breakdown of transformer oil insulation. The water impurity in oil, as the key factor for forming the carbonized conducting channel, initiates the electric breakdown process of transformer oil, which is dominated by thermal diffusion of water molecules. The increase of aging acid concentration will significantly promote the thermal diffusion of water impurities and the formation of an initial conducting channel, accounting for the degradation in dielectric strength of insulating oil containing water impurities after long-term operation of the transformer.

scholarly journals Characterization of design grammar of peptides for regulating liquid droplets and aggregates of FUS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyoto Kamagata ◽  
Rika Chiba ◽  
Ichiro Kawahata ◽  
Nanako Iwaki ◽  
Saori Kanbayashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Electrostatic Interactions ◽  
Amyloid Fibrils ◽  
Droplet Formation ◽  
Liquid Droplets ◽  
Proof Of Concept ◽  
Aggregate Formation ◽  
Fused In Sarcoma ◽  
Dynamics Simulations

AbstractLiquid droplets of aggregation-prone proteins, which become hydrogels or form amyloid fibrils, are a potential target for drug discovery. In this study, we proposed an experiment-guided protocol for characterizing the design grammar of peptides that can regulate droplet formation and aggregation. The protocol essentially involves investigation of 19 amino acid additives and polymerization of the identified amino acids. As a proof of concept, we applied this protocol to fused in sarcoma (FUS). First, we evaluated 19 amino acid additives for an FUS solution and identified Arg and Tyr as suppressors of droplet formation. Molecular dynamics simulations suggested that the Arg additive interacts with specific residues of FUS, thereby inhibiting the cation–π and electrostatic interactions between the FUS molecules. Second, we observed that Arg polymers promote FUS droplet formation, unlike Arg monomers, by bridging the FUS molecules. Third, we found that the Arg additive suppressed solid aggregate formation of FUS, while Arg polymer enhanced it. Finally, we observed that amyloid-forming peptides induced the conversion of FUS droplets to solid aggregates of FUS. The developed protocol could be used for the primary design of peptides controlling liquid droplets and aggregates of proteins.

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
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