Localization by site-directed mutagenesis of a galantamine binding site on α7 nicotinic acetylcholine receptor extracellular domain.

Galantamine is an approved drug treatment for Alzheimer's disease. Initially identified as a weak cholinesterase inhibitor, we have established that galantamine mainly acts as an 'allosterically potentiating ligand (APL)' of nicotinic acetylcholine receptors (nAChR). Meanwhile other 'positive allosteric modulators (PAM)' of nAChR channel activity have been discovered, and for one of them a binding site within the transmembrane domain has been proposed.

Structural model for the binding sites of allosterically potentiating ligands on nicotinic acetylcholine receptors.

Current treatments of Alzheimer's disease include the allosteric potentiation of nicotinic acetylcholine receptor (nAChR) response. The location of the binding site for allosteric potentiating ligands (APLs) within the receptor is not yet fully understood. Based on homology models for the ligand binding domain of human alpha7, human alpha4beta2, and chicken alpha7 receptors, as well as blind docking experiments with galanthamine, physostigmine, codeine, and 5HT, we identified T197 as an essential element of the APL binding site at the outer surface of the ligand binding domain (LBD) of nAChR.

Probing the nanosecond dynamics of a designed three-stranded beta-sheet with a massively parallel molecular dynamics simulation.

Recently a temperature-jump FTIR study of a designed three-stranded sheet showing a fast relaxation time of approximately 140 +/- 20 ns was published. We performed massively parallel molecular dynamics simulations in explicit solvent to probe the structural events involved in this relaxation. While our simulations produce similar relaxation rates, the structural ensemble is broad.

Accelerating molecular dynamic simulation on the cell processor and Playstation 3.

Implementation of molecular dynamics (MD) calculations on novel architectures will vastly increase its power to calculate the physical properties of complex systems. Herein, we detail algorithmic advances developed to accelerate MD simulations on the Cell processor, a commodity processor found in PlayStation 3 (PS3). In particular, we discuss issues regarding memory access versus computation and the types of calculations which are best suited for streaming processors such as the Cell, focusing on implicit solvation models.

Effects of long-range electrostatic forces on simulated protein folding kinetics.

Molecular dynamics simulations are a useful tool for characterizing protein folding pathways. There are several methods of treating electrostatic forces in these simulations with varying degrees of physical fidelity and computational efficiency. In this article, we compare the reaction field (RF) algorithm, particle-mesh Ewald (PME), and tapered cutoffs with increasing cutoff radii to address the impact of the electrostatics method employed on the folding kinetics.

Time resolved structure analysis of growing beta-amyloid fibers.

Formation of beta-amyloid plaques is a crucial feature of Alzheimer's disease. In the present work time resolved static light scattering was applied to investigate the size and shape of growing beta-amyloid aggregates preceding plaque formation. The beta-amyloid protein with 40 amino acid residues was used.

The Chemistry Development Kit (CDK): an open-source Java library for Chemo- and Bioinformatics.

The Chemistry Development Kit (CDK) is a freely available open-source Java library for Structural Chemo- and Bioinformatics. Its architecture and capabilities as well as the development as an open-source project by a team of international collaborators from academic and industrial institutions is described. The CDK provides methods for many common tasks in molecular informatics, including 2D and 3D rendering of chemical structures, I/O routines, SMILES parsing and generation, ring searches, isomorphism checking, structure diagram generation, etc.

Galanthamine as bis-functional ligand for the acetylcholinesterase.

Acetylcholinesterase plays a key role in the development of Alzheimer's disease as this enzyme is responsible for cleavage of the neurotransmitter acetylcholine, and, according to recent investigations, also promotes aggregation of beta-amyloid peptides, which causes plaque formation in synaptic areas. We have performed a molecular modeling study to investigate bis-galanthamine derivatives connected by a methylene spacer of varying length as dual acting acetylcholinesterase ligands. Our results suggest that such ligands indeed can interact simultaneously with both biological functions of the enzyme and should therefore serve as the basis for a further development of bis-functional Alzheimer drugs.