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This article describes the numerical solution of the time-dependent Smoluchowski equation to study diffusion in biomolecular systems. Specifically, finite element methods have been developed to calculate ligand binding rate constants for large biomolecules. The resulting software has been validated and applied to the mouse acetylcholinesterase (mAChE)(More)
We describe a chain of algorithms for molecular surface and volumetric mesh generation. We take as inputs the centers and radii of all atoms of a molecule and the toolchain outputs both triangular and tetrahedral meshes that can be used for molecular shape modeling and simulation. Experiments on a number of molecules are demonstrated, showing that our(More)
Most biological processes are initiated or mediated by the association of ligands and proteins. This work studies multistep, ligand-protein association processes by Brownian dynamics simulations with coarse-grained models for HIV-1 protease (HIVp) and its neutral ligands. We report the average association times when the ligand concentration is 100 μM. The(More)
Anthrax lethal factor (LF) is a critical virulence factor in the pathogenesis of anthrax. A structure-activity relationship (SAR) of potential lethal factor inhibitors (LFi) is presented in which the zinc-binding group (ZBG), linker, and backbone moieties for a series of hydroxypyrone-based compounds were systematically varied. It was found that(More)
Recently, researchers have used acetylcholinesterase (AChE) as a reaction vessel to synthesize its own inhibitors. Thus, 1 (syn-TZ2PA6), a femtomolar AChE inhibitor, which is formed in a 1:1 mixture with its anti-isomer by solution phase reaction from 3 (TZ2) and 4 (PA6), can be synthesized exclusively inside the AChE gorge. Our computational approach based(More)
Phosphorylation mediates the function of many proteins and enzymes. In the catalytic subunit of cAMP-dependent protein kinase, phosphorylation of Thr 197 in the activation loop strongly influences its catalytic activity. In order to provide theoretical understanding about this important regulatory process, classical molecular dynamics simulations and ab(More)
Human immunodeficiency virus type 1 (HIV-1) integrase is one of three virally encoded enzymes essential for replication and, therefore, a rational choice as a drug target for the treatment of HIV-1-infected individuals. In 2007, raltegravir became the first integrase inhibitor approved for use in the treatment of HIV-infected patients, more than a decade(More)
The reaction-diffusion system of the neuromuscular junction has been modeled in 3D using the finite element package FEtk. The numerical solution of the dynamics of acetylcholine with the detailed reaction processes of acetylcholinesterases and nicotinic acetylcholine receptors has been discussed with the reaction-determined boundary conditions. The(More)
The reaction mechanisms of two inhibitor TFK(+) and TFK(0) binding to H447I mutant mouse acetylcholinesterase (mAChE) have been investigated by using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach and classical molecular dynamics (MD) simulations. TFK(+) binding to the H447I mutant may proceed with a different reaction(More)
We have carried out density functional theory QM/MM calculations on the catalytic subunit of cAMP-dependent protein kinase (PKA). The QM/MM calculations indicate that the phosphorylation reaction catalyzed by PKA is mainly dissociative, and Asp166 serves as the catalytic base to accept the proton delivered by the substrate peptide. Among the key(More)