Computational and theoretical study of water and lipid dynamics in biomolecular systems

Title from PDF of title page (University of Missouri--Columbia, viewed on April 30, 2014).The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.VitaThis Ph.D. thesis describes three research projects in theoretical and computational biophysics aimed at studying the dynamics of water and lipid molecules in two distinct biomolecular systems. In the first project the energetics and dynamics of water transport through the aquaglyceroporin (GlpF) channel protein is studied by a combination of all-atom molecular dynamics (MD) simulations (both equilibrium and non-equilibrium MD) and stochastic modeling. The MD results are used to determine the potential of mean force and the diffusion coefficient of water molecules crossing the channel. Then, the latter quantities are used to estimate the intrinsic water flux through GlpF, and the corresponding channel permeability. In the second project, by employing a 0.1 micro second long, all-atom MD simulation, the self and correlated dynamics of lipid atoms and molecules in a fully hydrated DMPC lipid bilayer is investigated. The MD simulation results are used to develop a memory function based approach for accurately calculating the lateral self-diffusion coefficient of lipids. In some cases, the proposed memory function method provides a better approach than the currently used ones for determining the lateral diffusion coefficient of lipids in lipid bilayers from the dynamic structure factor measured in inelastic neutron scattering experiments. The purpose of the third project is to investigate the dynamics of water molecules in a hydrated lipid membrane. Using the same MD simulation as in the second project, the anomalous properties of buried and hydration waters (located at the proximity of the fluctuating surface of the lipid membrane) are revealed and contrasted to the properties of bulk water

A modified PATH algorithm rapidly generates transition states comparable to those found by other well established algorithms

PATH rapidly computes a path and a transition state between crystal structures by minimizing the Onsager-Machlup action. It requires input parameters whose range of values can generate different transition-state structures that cannot be uniquely compared with those generated by other methods. We outline modifications to estimate these input parameters to circumvent these difficulties and validate the PATH transition states by showing consistency between transition-states derived by different algorithms for unrelated protein systems. Although functional protein conformational change trajectories are to a degree stochastic, they nonetheless pass through a well-defined transition state whose detailed structural properties can rapidly be identified using PATH

Motional Coherence in Fluid Phospholipid Membranes

URL:http://link.aps.org/doi/10.1103/PhysRevLett.101.248106 DOI:10.1103/PhysRevLett.101.248106We report a high energy-resolution neutron backscattering study, combined with in situ diffraction, to investigate slow molecular motions on nanosecond time scales in the fluid phase of phospholipid bilayers of 1,2-dimyristoyl-sn-glycero-3-phoshatidylcholine. A cooperative structural relaxation process was observed. From the in-plane scattering vector dependence of the relaxation rates in hydrogenated and deuterated samples, combined with results from a 0.1  μs long all-atom molecular dynamics simulation, it is concluded that correlated dynamics in lipid membranes occurs over several lipid distances, spanning a time interval from pico- to nanoseconds.We acknowledge financial support from the DFG through Project No. SA 772/8-2

Subdiffusion and lateral diffusion coefficient of lipid atoms and molecules in phospholipid bilayers

We use a long, all-atom molecular dynamics (MD) simulation combined with theoretical modeling to investigate the dynamics of selected lipid atoms and lipid molecules in a hydrated diyristoyl-phosphatidylcholine (DMPC) lipid bilayer. From the analysis of a 0.1 $\mu$s MD trajectory we find that the time evolution of the mean square displacement, [\delta{r}(t)]^2, of lipid atoms and molecules exhibits three well separated dynamical regions: (i) ballistic, with [\delta{r}(t)]^2 ~ t^2 for t < 10 fs; (ii) subdiffusive, with [\delta{r}(t)]^2 ~ t^{\beta} with \beta<1, for 10 ps < t < 10 ns; and (iii) Fickian diffusion, with [\delta{r}(t)]^2 ~ t for t > 30 ns. We propose a memory function approach for calculating [\delta{r}(t)]^2 over the entire time range extending from the ballistic to the Fickian diffusion regimes. The results are in very good agreement with the ones from the MD simulations. We also examine the implications of the presence of the subdiffusive dynamics of lipids on the self-intermediate scattering function and the incoherent dynamics structure factor measured in neutron scattering experiments.Comment: Submitted to Phys. Rev.

Efficacy and safety of anti-malarial drugs (chloroquine and hydroxy-chloroquine) in treatment of COVID-19 infection: a systematic review and meta-analysis

Background: Anti-malarial drugs inhibit coronaviruses in-vitro. Few published studies have evaluated the safety and efficacy of these drugs in the treatment of COVID-19 infection. Materials and Methods: This is a systematic review and meta-analysis of clinical trials and observational studies. Major database searches were carried out up until June 5, 2020. Participants admitted with RT-PCR-confirmed SARS Cov-2 (COVID-19) infection were included. The “Intervention group” received anti-malarial drugs with or without other drugs (Azithromycin) administered as an adjunct to the standard treatment/care. The “Control group” received treatment except anti-malarial drugs. The primary outcome is “all-cause mortality.” Secondary outcome measures were effects on clinical and laboratory parameters and adverse events. Results: Of 3,472 citations, 17 (six clinical trials and 11 observational studies) studies provided data of 8,071 participants. Compared to the control, Hydroxy-chloroquine (HCQ) has no significant effect on mortality [(OR 0.87; 95% CI 0.46–1.64); eight observational studies; N = 5,944]. Data from a single, small non-randomized trial (N = 42) also reached a similar conclusion (OR 1.94; 95% CI 0.07–50.57; p = 0.69). Compared to the control, HCQ plus Azithromycin (AZM) significantly increased mortality [(OR 2.84; 95% CI 2.19–3.69); four observational studies; N = 2,310]. Compared to the control, risk of any adverse event was significantly increased in HCQ group [(OR 3.35; 95% CI 1.58–7.13); four clinical trials; N = 263]. Compared to control, risk of adverse cardiac events (abnormal ECG, arrhythmia, or QT prolongation) were not significantly increased in HCQ group (but significantly increased in the HCQ plus AZM group). The GRADE evidence generated for all the outcomes was of “very low-quality.” Conclusions: As very low quality evidence suggests an increased risk of mortality and adverse event with HCQ plus Azithromycin combination (not HCQ alone), caution should be exercised while prescribing this combination for treatment of hospitalized adults with COVID-19 infection. Good quality, multi-centric RCTs (including both hospitalized and non-hospitalized patients) are required for any firm recommendation to be made during the ongoing pandemic. OSF Protocol Registration Link: https://osf.io/6zxsu

Impact of sanitizers on quality of Lipase and Triglyceride analytes in clinical laboratory

Use of sanitizers in diagnostic centres causes derangement in quality control values of lipase and triglycerides (TG) analytes during COVID-19. Our study provides a practical insight into the type of sanitizers to be used in a laboratory. Performance Verifier (PV) and reagents (lipase and TG) were contaminated with sanitizer and 70% isopropyl alcohol. Groups formed were- PVNet (G1), PV with Sanitizer (G2), PV with 70% Alcohol (G3), Sanitizer contaminated reagent (G4). Controls PV-1 and PV-2 were run. ANOVA and Tukey’s test among groups and between groups were compared. Significant difference in mean PV-1and PV-2 values of TG [PV-1, PV-2 (P &lt;0.0001)] and lipase TG [PV-1 P &lt;0.0001) PV-2 P &lt;0.001] among all tested groups were observed. Between-group analysis showed significantly higher PV-1 and PV-2 values in sanitizer contaminated PV group (P &lt;0.001) compared to Neat PVs (P &lt;0.001), and PVs contaminated with 70% alcohol (P &lt;0.001). sanitizer contaminated PV-1 values were significantly higher when compared to Neat PV-1 (P &lt;0.001)for lipase. It is advised that isopropyl alcohol (70%) should be preferred over glycerol containing sanitizers to reduce pre-analytical errors for lipase and TG estimation

Impact of sanitizers on quality of Lipase and Triglyceride analytes in clinical laboratory

701-706Use of sanitizers in diagnostic centres causes derangement in quality control values of lipase and triglycerides (TG) analytes during COVID-19. Our study provides a practical insight into the type of sanitizers to be used in a laboratory. Performance Verifier (PV) and reagents (lipase and TG) were contaminated with sanitizer and 70% isopropyl alcohol. Groups formed were- PVNet (G1), PV with Sanitizer (G2), PV with 70% Alcohol (G3), Sanitizer contaminated reagent (G4). Controls PV-1 and PV-2 were run. ANOVA and Tukey’s test among groups and between groups were compared. Significant difference in mean PV-1and PV-2 values of TG [PV-1, PV-2 (P P P P P P P <0.001)for lipase. It is advised that isopropyl alcohol (70%) should be preferred over glycerol containing sanitizers to reduce pre-analytical errors for lipase and TG estimation

Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients

Dynamics of Hot QCD Matter -- Current Status and Developments

The discovery and characterization of hot and dense QCD matter, known as Quark Gluon Plasma (QGP), remains the most international collaborative effort and synergy between theorists and experimentalists in modern nuclear physics to date. The experimentalists around the world not only collect an unprecedented amount of data in heavy-ion collisions, at Relativistic Heavy Ion Collider (RHIC), at Brookhaven National Laboratory (BNL) in New York, USA, and the Large Hadron Collider (LHC), at CERN in Geneva, Switzerland but also analyze these data to unravel the mystery of this new phase of matter that filled a few microseconds old universe, just after the Big Bang. In the meantime, advancements in theoretical works and computing capability extend our wisdom about the hot-dense QCD matter and its dynamics through mathematical equations. The exchange of ideas between experimentalists and theoreticians is crucial for the progress of our knowledge. The motivation of this first conference named "HOT QCD Matter 2022" is to bring the community together to have a discourse on this topic. In this article, there are 36 sections discussing various topics in the field of relativistic heavy-ion collisions and related phenomena that cover a snapshot of the current experimental observations and theoretical progress. This article begins with the theoretical overview of relativistic spin-hydrodynamics in the presence of the external magnetic field, followed by the Lattice QCD results on heavy quarks in QGP, and finally, it ends with an overview of experiment results.Comment: Compilation of the contributions (148 pages) as presented in the `Hot QCD Matter 2022 conference', held from May 12 to 14, 2022, jointly organized by IIT Goa & Goa University, Goa, Indi

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe