Biomedical subjects

M Elstner

Publications and source records attributed to M Elstner.

9 recordsLinked to original sources

PubMed2006

Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial.

Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson's Disease Rating Scale scores or dopamine transporter SPECT.

Administration, Oral↗

PubMed2006

Toward theoretical analysis of long-range proton transfer kinetics in biomolecular pumps.

Motivated by the long-term goal of theoretically analyzing long-range proton transfer (PT) kinetics in biomolecular pumps, researchers made a number of technical developments in the framework of quantum mechanics-molecular mechanics (QM/MM) simulations. A set of collective reaction coordinates is proposed for characterizing the progress of long-range proton transfers; unlike previous suggestions, the new coordinates can describe PT along highly nonlinear three-dimensional pathways. Calculations using a realistic model of carbonic anhydrase demonstrated that adiabatic mapping using these collective coordinates gives reliable energetics and critical geometrical parameters as compared to minimum energy path calculations, which suggests that the new coordinates can be effectively used as reaction coordinate in potential of mean force calculations for long-range PT in complex systems. In addition, the generalized solvent boundary potential was implemented in the QM/MM framework for rectangular geometries, which is useful for studying reactions in membrane systems. The resulting protocol was found to produce water structure in the interior of aquaporin consistent with previous studies including a much larger number of explicit solvent and lipid molecules. The effect of electrostatics for PT through a membrane protein was also illustrated with a simple model channel embedded in different dielectric continuum environments. The encouraging results observed so far suggest that robust theoretical analysis of long-range PT kinetics in biomolecular pumps can soon be realized in a QM/MM framework.

Aquaporins↗

PubMed2005

Simulation of water cluster assembly on a graphite surface.

The assembly of small water clusters (H2O)n, n = 1-6, on a graphite surface is studied using a density functional tight-binding method complemented with an empirical van der Waals force correction, with confirmation using second-order Møller-Plesset perturbation theory. It is shown that the optimized geometry of the water hexamer may change its original structure to an isoenergy one when interacting with a graphite surface in some specific orientation, while the smaller water cluster will maintain its cyclic or linear configurations (for the water dimer). The binding energy of water clusters interacting with graphite is dependent on the number of water molecules that form hydrogen bonds, but is independent of the water cluster size. These physically adsorbed water clusters show little change in their IR peak position and leave an almost perfect graphite surface.

Journal Article↗

PubMed2005

Calculating absorption shifts for retinal proteins: computational challenges.

Rhodopsins can modulate the optical properties of their chromophores over a wide range of wavelengths. The mechanism for this spectral tuning is based on the response of the retinal chromophore to external stress and the interaction with the charged, polar, and polarizable amino acids of the protein environment and is connected to its large change in dipole moment upon excitation, its large electronic polarizability, and its structural flexibility. In this work, we investigate the accuracy of computational approaches for modeling changes in absorption energies with respect to changes in geometry and applied external electric fields. We illustrate the high sensitivity of absorption energies on the ground-state structure of retinal, which varies significantly with the computational method used for geometry optimization. The response to external fields, in particular to point charges which model the protein environment in combined quantum mechanical/molecular mechanical (QM/MM) applications, is a crucial feature, which is not properly represented by previously used methods, such as time-dependent density functional theory (TDDFT), complete active space self-consistent field (CASSCF), and Hartree-Fock (HF) or semiempirical configuration interaction singles (CIS). This is discussed in detail for bacteriorhodopsin (bR), a protein which blue-shifts retinal gas-phase excitation energy by about 0.5 eV. As a result of this study, we propose a procedure which combines structure optimization or molecular dynamics simulation using DFT methods with a semiempirical or ab initio multireference configuration interaction treatment of the excitation energies. Using a conventional QM/MM point charge representation of the protein environment, we obtain an absorption energy for bR of 2.34 eV. This result is already close to the experimental value of 2.18 eV, even without considering the effects of protein polarization, differential dispersion, and conformational sampling.

Absorption↗

PubMed2004

A global investigation of excited state surfaces within time-dependent density-functional response theory.

This work investigates the capability of time-dependent density functional response theory to describe excited state potential energy surfaces of conjugated organic molecules. Applications to linear polyenes, aromatic systems, and the protonated Schiff base of retinal demonstrate the scope of currently used exchange-correlation functionals as local, adiabatic approximations to time-dependent Kohn-Sham theory. The results are compared to experimental and ab initio data of various kinds to attain a critical analysis of common problems concerning charge transfer and long range (nondynamic) correlation effects. This analysis goes beyond a local investigation of electronic properties and incorporates a global view of the excited state potential energy surfaces.

Journal Article↗

PubMed2001

Quantum mechanics simulation of protein dynamics on long timescale.

Protein structure and dynamics are the keys to a wide range of problems in biology. In principle, both can be fully understood by using quantum mechanics as the ultimate tool to unveil the molecular interactions involved. Indeed, quantum mechanics of atoms and molecules have come to play a central role in chemistry and physics. In practice, however, direct application of quantum mechanics to protein systems has been prohibited by the large molecular size of proteins. As a consequence, there is no general quantum mechanical treatment that not only exceeds the accuracy of state-of-the-art empirical models for proteins but also maintains the efficiency needed for extensive sampling in the conformational space, a requirement mandated by the complexity of protein systems. Here we show that, given recent developments in methods, a general quantum mechanical-based treatment can be constructed. We report a molecular dynamics simulation of a protein, crambin, in solution for 350 ps in which we combine a semiempirical quantum-mechanical description of the entire protein with a description of the surrounding solvent, and solvent-protein interactions based on a molecular mechanics force field. Comparison with a recent very high-resolution crystal structure of crambin (Jelsch et al., Proc Natl Acad Sci USA 2000;102:2246-2251) shows that geometrical detail is better reproduced in this simulation than when several alternate molecular mechanics force fields are used to describe the entire system of protein and solvent, even though the structure is no less flexible. Individual atomic charges deviate in both directions from "canonical" values, and some charge transfer is found between the N and C-termini. The capability of simulating protein dynamics on and beyond the few hundred ps timescale with a demonstrably accurate quantum mechanical model will bring new opportunities to extend our understanding of a range of basic processes in biology such as molecular recognition and enzyme catalysis.

Alanine↗

PubMed2001

Tetragonal crystalline carbon nitrides: theoretical predictions.

New tetragonal phases of crystalline carbon nitride (CN) and their atomic structures have been identified using a self-consistent-charge density-functional tight-binding method. A tetragonal rocksalt structure provides theoretical support to recent experimental evidence for a stoichiometric CN phase with tetragonal symmetry. A body-centered tetragonal CN phase with 1:1 stoichiometry is predicted to be highly stable and of interesting atomic structure with complicated C-C and N-N dimerizations along the c axis. The cubic-to-tetragonal transitions are carefully examined to understand the underlying mechanism.

Journal Article↗

PubMed2000

Glyceraldehyde-3-phosphate dehydrogenase in neurodegeneration and apoptosis signaling.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a well-studied glycolytic enzyme that plays a key role in energy metabolism. GAPDH catalyzes the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate in the glycolytic pathway. As part of the conversion, GAPDH converts NAD+ to the high-energy electron carrier NADH. GAPDH has been referred to as a "housekeeping" protein and based on the view that GAPDH gene expression remains constant under changing cellular conditions, the levels of GAPDH mRNA have frequently been used to normalize northern blots. In recent years, that view has changed since GAPDH is now known to contribute to a number of diverse cellular functions unrelated to glycolysis. Normative functions of GAPDH now include nuclear RNA export, DNA replication, DNA repair, exocytotic membrane fusion, cytoskeletal organization and phosphotransferase activity. Pathologically, GAPDH has been implicated in apoptosis, neurodegenerative disease, prostate cancer and viral pathogenesis (see Sirover (1999) for a recent review of GAPDH functions). Most recently, it has been shown that GAPDH is a target for deprenyl related compounds (Carlile et al., 2000; Kragten et al., 1998) and may contribute to the neuroprotection offered by those compounds.

Animals↗

PubMedDate not supplied

Pro- and antioxidative properties of cortical tissue preparations from human brain exhibiting NMDA-receptor characteristics.

The effects of cortical tissue preparations (CTP) from human brain on the production of reactive oxygen species (ROS) has been investigated with several biochemical model reactions. As indicators for ROS, fragmentation of the methionine derivatives, alpha-keto-gamma-methylthiobutyric acid (KMB) or 1-amino-cyclopropane-1-carboxylic acid (ACC), yielding ethene have been used. With these systems we have shown that production of OH-radical-type oxidants by the xanthine oxidase (XOD)-system is strongly stimulated by CTP. This activity is due to intrinsic iron ions since ethene formation from KMB is stimulated by EDTA, inhibited by desferrioxamine (Desferal) and also visible with heat-denatured CTP. CTP by themselves have no XOD activity. 3-Hydroxykynurenine (3HK) is another possible substrate for XOD but produces H2O2 without XOD-catalysis, whereas allopurinol is not inhibiting. CTP contain measurable NAD(P)H oxidoreductase activity, producing OH- radical- type oxidants at the expense of NADPH and (to a lesser extent) NADH as electron donors, shown as redox-cycling of 2-methyl-5-hydroxy-1,4-naphthoquinone, plumbagin. Ethene formation from KMB is also driven by both morpholinosydnonimine (SIN) or ONOOH. The reaction driven by SIN is stimulated by CTP and inhibited by catalase, SOD and hemoglobin. Since ethene release from KMB driven by ONOOH is inhibited by CTP the mechanisms driving KMB fragmentation are different for SIN and ONOOH. Furthermore CTP contain approx. 4 U catalase activity per mg protein and very weak peroxidase (POD) activity shown as ACC fragmentation yielding ethene in the presence of both H2O2 and KBr or NaCl. Since ACC binds to CTP and both compounds, ACC and KMB are natural products, present in food (ACC) or synthesized from methionine in vivo (KMB), these compounds may represent protecting agents in systems where reactive oxygen species are formed. One might even speculate that the production of ethene at these membrane receptor sites may have biological functions, since ethene is known to possess anaesthetic activities.

Antioxidants↗