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Sökning: WFRF:(Berk M.)

  • Resultat 21-29 av 29
  • Föregående 12[3]
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21.
  • Ghiringhelli, Luca M, et al. (författare)
  • Competing adsorption between hydrated peptides and water onto metal surfaces : from electronic to conformational properties
  • 2008
  • Ingår i: Journal of the American Chemical Society. - 0002-7863 .- 1520-5126. ; 130:40, s. 13460-13464
  • Tidskriftsartikel (refereegranskat)abstract
    • Inorganic-(bio)organic interfaces are of central importance in many fields of current research. Theoretical and computational tools face the difficult problem of the different time and length scales that are involved and linked in a nontrivial way. In this work, a recently proposed hierarchical quantum-classical scale-bridging approach is further developed to study large flexible molecules. The approach is then applied to study the adsorption of oligopeptides on a hydrophilic Pt(111) surface under complete wetting conditions. We examine histidine sequences, which are well known for their binding affinity to metal surfaces. Based on a comparison with phenylalanine, which binds as strong as histidine under high vacuum conditions but, as we show, has no surface affinity under wet conditions, we illustrate the mediating effects of near-surface water molecules. These contribute significantly to the mechanism and strength of peptide binding. In addition to providing physical-chemical insights in the mechanism of surface binding, our computational approach provides future opportunities for surface-specific sequence design.
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22.
  • Kasson, Peter M., et al. (författare)
  • Probing microscopic material properties inside simulated membranes through spatially resolved three-dimensional local pressure fields and surface tensions
  • 2013
  • Ingår i: Chemistry and Physics of Lipids. - 0009-3084. ; 169, s. 106-112
  • Tidskriftsartikel (refereegranskat)abstract
    • Cellular lipid membranes are spatially inhomogeneous soft materials. Materials properties such as pressure and surface tension thus show important microscopic-scale variation that is critical to many biological functions. We present a means to calculate pressure and surface tension in a 3D-resolved manner within molecular-dynamics simulations and show how such measurements can yield important insight. We also present the first corrections to local virial and pressure fields to account for the constraints typically used in lipid simulations that otherwise cause problems in highly oriented systems such as bilayers. Based on simulations of an asymmetric bacterial ion channel in a POPC bilayer, we demonstrate how 3D-resolved pressure can probe for both short-range and long-range effects from the protein on the membrane environment. We also show how surface tension is a sensitive metric for inter-leaflet equilibrium and can be used to detect even subtle imbalances between bilayer leaflets in a membrane-protein simulation. Since surface tension is known to modulate the function of many proteins, this effect is an important consideration for predictions of ion channel function. We outline a strategy by which our local pressure measurements, which we make available within a version of the GROMACS simulation package, may be used to design optimally equilibrated membrane-protein simulations.
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23.
  • Kasson, Peter M., et al. (författare)
  • Probing microscopic material properties inside simulated membranes through spatially resolved three-dimensional local pressure fields and surface tensions
  • 2013
  • Ingår i: Chemistry and Physics of Lipids. - 0009-3084 .- 1873-2941. ; 169, s. 106-112
  • Tidskriftsartikel (refereegranskat)abstract
    • Cellular lipid membranes are spatially inhomogeneous soft materials. Materials properties such as pressure and surface tension thus show important microscopic-scale variation that is critical to many biological functions. We present a means to calculate pressure and surface tension in a 3D-resolved manner within molecular-dynamics simulations and show how such measurements can yield important insight. We also present the first corrections to local virial and pressure fields to account for the constraints typically used in lipid simulations that otherwise cause problems in highly oriented systems such as bilayers. Based on simulations of an asymmetric bacterial ion channel in a POPC bilayer, we demonstrate how 3D-resolved pressure can probe for both short-range and long-range effects from the protein on the membrane environment. We also show how surface tension is a sensitive metric for inter-leaflet equilibrium and can be used to detect even subtle imbalances between bilayer leaflets in a membrane-protein simulation. Since surface tension is known to modulate the function of many proteins, this effect is an important consideration for predictions of ion channel function. We outline a strategy by which our local pressure measurements, which we make available within a version of the GROMACS simulation package, may be used to design optimally equilibrated membrane-protein simulations.
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24.
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25.
  • Pronk, Sander, et al. (författare)
  • GROMACS 4.5 : a high-throughput and highly parallel open source molecular simulation toolkit
  • 2013
  • Ingår i: Bioinformatics. - 1367-4803. ; 29:7, s. 845-854
  • Tidskriftsartikel (refereegranskat)abstract
    • Motivation: Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic and structural data are changing this by enabling large-scale automated simulation of, for instance, many conformers or mutants of biomolecules with or without a range of ligands. At the same time, advances in performance and scaling now make it possible to model complex biomolecular interaction and function in a manner directly testable by experiment. These applications share a need for fast and efficient software that can be deployed on massive scale in clusters, web servers, distributed computing or cloud resources. Results: Here, we present a range of new simulation algorithms and features developed during the past 4 years, leading up to the GROMACS 4.5 software package. The software now automatically handles wide classes of biomolecules, such as proteins, nucleic acids and lipids, and comes with all commonly used force fields for these molecules built-in. GROMACS supports several implicit solvent models, as well as new free-energy algorithms, and the software now uses multithreading for efficient parallelization even on low-end systems, including windows-based workstations. Together with hand-tuned assembly kernels and state-of-the-art parallelization, this provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations.
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26.
  • Pronk, Sander, et al. (författare)
  • GROMACS 4.5 a high-throughput and highly parallel open source molecular simulation toolkit
  • 2013
  • Ingår i: Bioinformatics. - 1367-4803 .- 1367-4811. ; 29:7, s. 845-854
  • Tidskriftsartikel (refereegranskat)abstract
    • Motivation: Molecular simulation has historically been a low-throughput technique, but faster computers and increasing amounts of genomic and structural data are changing this by enabling large-scale automated simulation of, for instance, many conformers or mutants of biomolecules with or without a range of ligands. At the same time, advances in performance and scaling now make it possible to model complex biomolecular interaction and function in a manner directly testable by experiment. These applications share a need for fast and efficient software that can be deployed on massive scale in clusters, web servers, distributed computing or cloud resources. Results: Here, we present a range of new simulation algorithms and features developed during the past 4 years, leading up to the GROMACS 4.5 software package. The software now automatically handles wide classes of biomolecules, such as proteins, nucleic acids and lipids, and comes with all commonly used force fields for these molecules built-in. GROMACS supports several implicit solvent models, as well as new free-energy algorithms, and the software now uses multithreading for efficient parallelization even on low-end systems, including windows-based workstations. Together with hand-tuned assembly kernels and state-of-the-art parallelization, this provides extremely high performance and cost efficiency for high-throughput as well as massively parallel simulations.
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27.
  • Seibert, M. Marvin, et al. (författare)
  • Reproducible polypeptide folding and structure prediction using molecular dynamics simulations
  • 2005
  • Ingår i: Journal of Molecular Biology. - 0022-2836 .- 1089-8638. ; 354:1, s. 173-183
  • Tidskriftsartikel (refereegranskat)abstract
    • The folding of a polypeptide from an extended state to a well-defined conformation is studied using microsecond classical molecular dynamics (MD) simulations and replica exchange molecular dynamics (REMD) simulations in explicit solvent and in vacuo. It is shown that the solvated peptide folds many times in the REMD simulations but only a few times in the conventional simulations. From the folding events in the classical simulations we estimate an approximate folding time of 1-2 micros. The REMD simulations allow enough sampling to deduce a detailed Gibbs free energy landscape in three dimensions. The global minimum of the energy landscape corresponds to the native state of the peptide as determined previously by nuclear magnetic resonance (NMR) experiments. Starting from an extended state it takes about 50 ns before the native structure appears in the REMD simulations, about an order of magnitude faster than conventional MD. The calculated melting curve is in good qualitative agreement with experiment. In vacuo, the peptide collapses rapidly to a conformation that is substantially different from the native state in solvent.
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28.
  • Solomon, Scott D., et al. (författare)
  • Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis : Analysis of the APOLLO Study
  • 2019
  • Ingår i: Circulation. - Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 139:4, s. 431-443
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed.Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness 13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis.Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference SEM: -0.90.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3 +/- 3.9 mL, P=0.036), decreased global longitudinal strain (-1.4 +/- 0.6%, P=0.015), and increased cardiac output (0.38 +/- 0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01).Conclusions: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis.
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29.
  • Suhr, Ole B., et al. (författare)
  • Efficacy and safety of patisiran for familial amyloidotic polyneuropathy : a phase II multi-dose study
  • 2015
  • Ingår i: Orphanet Journal of Rare Diseases. - 1750-1172. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development.
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