Remodeling the Conformational Dynamics of I-motif DNA by Helicases in ATP-independent Mode at Acidic Environment

In light of the high affinity of Cu2+ for Alzheimer's Aβ1–42 and its ability to subsequently catalyze the formation of radicals, we examine the effects of Cu2+ binding, Aβ oxidation, and an acidic environment on the conformational dynamics of the smallest Aβ1–42 oligomer, the Aβ1–42 dimer.

Download Full-text

pH Dependent Release Potential of Natural Polymers in Sustained Release of Ornidazole From Colon Targeted Delivery System)

International Journal of Drug Delivery Technology ◽

10.25258/ijddt.9.2.4 ◽

2019 ◽

Vol 9 (02) ◽

Author(s):

Sharma Pankaj ◽

Tailang Mukul

Keyword(s):

Drug Release ◽

Delivery System ◽

Targeted Delivery ◽

Guar Gum ◽

Acidic Environment ◽

Natural Polymers ◽

Weight Variation ◽

Curve Determination ◽

Preformulation Studies

The aim of present work was to prepare colon specific delivery system of Ornidazole using different ratio of shellac, zein and guar gum. From study of various literature it revealed that shellac, zein and guar gum released drug from dosage form at the pH of 6.9, 11.5, 7-9 respectively. The main problem associated with colon targeted drug delivery system is degradation of drug in the acidic environment of stomach to circumvent the present problem different combinations of shellac, zein and guar gum were employed in the formulation of colon targeted tablet. Several preformulation parameters were determined such as melting point, FTIR spectroscopy, preparation of calibration curve, determination of λmax and partition coefficient. After the preformulation studies, next steps were preparation of core tablets, evaluation of core of tablets and coating of tablets. The data obtained from preformulation study seven formulations were developed and evaluated for various parameters. Based on evaluated parameter such as weight variation, friability, dissolution study, invitro drug release etc. the F7 formulation show better results colon targeted tablets. Drug content in F7 formulation was 95% and drug release after 6 hrs was 96%. Formulation containing combination of shellac, zein and guar gum released least amount of drug in the acidic environment of stomach and released most of the drug in colon. It is evide

Download Full-text

Constant pH Molecular Dynamics Reveals How Proton Release Drives the Conformational Transition of a Transmembrane Efflux Pump

10.26434/chemrxiv.5496907 ◽

2017 ◽

Author(s):

Jana Shen ◽

Zhi Yue ◽

Helen Zgurskaya ◽

Wei Chen

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Transmembrane Domain ◽

Conformational Transition ◽

Conformational Dynamics ◽

Proton Release ◽

Intrinsic Resistance ◽

Constant Ph ◽

Wide Range ◽

Constant Ph Molecular Dynamics

AcrB is the inner-membrane transporter of E. coli AcrAB-TolC tripartite efflux complex, which plays a major role in the intrinsic resistance to clinically important antibiotics. AcrB pumps a wide range of toxic substrates by utilizing the proton gradient between periplasm and cytoplasm. Crystal structures of AcrB revealed three distinct conformational states of the transport cycle, substrate access, binding and extrusion, or loose (L), tight (T) and open (O) states. However, the specific residue(s) responsible for proton binding/release and the mechanism of proton-coupled conformational cycling remain controversial. Here we use the newly developed membrane hybrid-solvent continuous constant pH molecular dynamics technique to explore the protonation states and conformational dynamics of the transmembrane domain of AcrB. Simulations show that both Asp407 and Asp408 are deprotonated in the L/T states, while only Asp408 is protonated in the O state. Remarkably, release of a proton from Asp408 in the O state results in large conformational changes, such as the lateral and vertical movement of transmembrane helices as well as the salt-bridge formation between Asp408 and Lys940 and other sidechain rearrangements among essential residues.Consistent with the crystallographic differences between the O and L protomers, simulations offer dynamic details of how proton release drives the O-to-L transition in AcrB and address the controversy regarding the proton/drug stoichiometry. This work offers a significant step towards characterizing the complete cycle of proton-coupled drug transport in AcrB and further validates the membrane hybrid-solvent CpHMD technique for studies of proton-coupled transmembrane proteins which are currently poorly understood.

Download Full-text

Molecular Basis of Glucose Transport Mechanism in Plants

10.26434/chemrxiv.8049848.v1 ◽

2019 ◽

Cited By ~ 2

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

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.

Download Full-text

Inhibition of pipeline steel corrosion in acidic environment using sulphadoxine and pyrimethamine

10.31221/osf.io/854v9 ◽

2019 ◽

Author(s):

Chem Int

Keyword(s):

Inhibition Efficiency ◽

Pipeline Steel ◽

Electrochemical Techniques ◽

Steel Corrosion ◽

Acidic Environment ◽

Inhibitor Concentration ◽

Adsorption Data ◽

Corrosion Inhibition Efficiency ◽

Inhibitive Action ◽

Sulphadoxine Pyrimethamine

The anti-corrosive properties of sulphadoxine + pyrimethamine (S+P) on the corrosion of pipeline steel in acidic environment were investigated using electrochemical techniques. The results obtained showed an excellent inhibition efficiency which increased with increase in inhibitor concentration. The corrosion inhibition efficiency increased up to 99.04 % at 0.01M S+P and decreased with rise in temperature down to 85.93 % at 333 K and 0.01 M S+P, suggesting a physiosorptive mechanism of adsorption. Also the adsorption data was fitted into Langmuir and Temkin adsorption isotherms, while the inhibitive action was shown to proceed by mixed inhibition mode.

Download Full-text

Monitoring the Structural Dynamics of U2 snRNA Via Single-Molecule Förster Resonance Energy Transfer

10.31237/osf.io/9j8gq ◽

2018 ◽

Author(s):

Alexander Carl DeHaven

Keyword(s):

Energy Transfer ◽

Structural Dynamics ◽

Single Molecule ◽

Conformational Dynamics ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Förster Resonance Energy Transfer ◽

U2 Snrna ◽

Folding Dynamics ◽

The Impact

This thesis contains four topic areas: a review of single-molecule microscropy methods and splicing, conformational dynamics of stem II of the U2 snRNA, the impact of post-transcriptional modifications on U2 snRNA folding dynamics, and preliminary findings on Mango aptamer folding dynamics.

Download Full-text