Three-dimensional structure of cofilin bound to monomeric actin derived by structural mass spectrometry data

The mission of the National Biomedical Computation Resource (NBCR) is to conduct, catalyze and enable multiscale biomedical research by harnessing advanced computation and data cyberinfrastructure through multidiscipline and multi-institutional integrative research and development activities. Here we report some recent advances enabled by tools from NBCR at multiple scales of biological investigation towards simulation based medicine for human diseases such as heart failure, neuromuscular dysfunction and Alzheimer’s disease. Continuity is a multiscale problem solving environment in bioengineering and physiology, especially cardiac biomechanics, biotransport and electrophysiology. Using noninvasive magnetic resonance imaging (MRI) and invasive catheter techniques, followed by finite element (FE) modeling of the obtained data using Continuity 6.3, Costandi et al were able to estimate the end diastolic volume pressure relationship (EDVPR) in the dilatation phase. The geometric data at the end-diastole from MRI and the pressure and volume data provided by the hemodynamic analysis were used to simulate computationally the systolic phase while maintaining the conservation of mass. The results together suggest that while there is initial compensation of heart function from dilatation in muscle LIM protein (MLP) deficient mice, eventually this fails (decompensation) completely in adults, possibly due to further increase beyond a certain threshold in the stiffness of the myocardium. Neuromuscular dysfunction is a common pathological condition in many autoimmune diseases such as Lou Gehrig’s or myasthenia gravis. To simulate physiological conditions where the ligand and enzyme concentrations are not at steady state but time-dependent, Cheng et al developed a FE solver based on the Finite Element ToolKit (FETK) for the time-dependent Smoluchowski equation to model the mouse Acetylcholinesterase (AchE) system, a diffusionlimited reaction with plenty of real experimental data for validation of models. The biomolecular mesh representation was generated using the Levelset Boundary Interior Exterior Mesher (LBIE). The calculations depend on the FETK and the Adaptive Poisson-Boltzmann Solver (APBS) for electrostatic potentials and for iterative mesh refinement to gain better accuracy in the binding constant calculation. This new tool establishes the foundation for integration of molecular scale studies into larger simulations at the cellular scale such as the neuromuscular junction, where AchE plays a critical role in neurotransmitter signaling pathways. AutoDock is one of the most cited docking software in a recent literature survey, and AutoDockTools is an important user interface designed by NBCR to facilitate the preparation, execution and analysis of AutoDock studies. Eubank et al recently found that one of the major chemical ingredients found in marijuana, Δ−tetrahydrocannabinol (THC), binds the peripheral anionic site of acetylcholinesterase (AchE) using AutoDock, and the result is subsequently confirmed through enzymatic inhibition assays. As AchE is implicated in accelerating the formation of amyloid fibrils in Alzheimer’s disease, this collaborative study suggests that THC and its analogues may lead to the design of better therapeutics which may improve neurotransmitter stability and prevent amyloid formation. Additional information about the cyberenvironment for multiscale modeling and translational research from NBCR may be found at http://nbcr.net/tools.php and http://nbcr.net/news.php.