The mission of the National Biomedical Computation Resource (NBCR) is to conduct, catalyze, and enable biomedical research by harnessing forefront information technologies to advance mechanistic understanding in multi-scale biomedical problems that integrate diverse structural and functional measurements and span scales of biological organization from molecule to organ system. A central theme of NBCR has been the development and deployment of tools and infrastructure that enable biomedical problems to be addressed using mechanistic, structure- and physics-driven computational models that span scales of biological organization from atomistic simulations of molecular dynamics to continuum simulations of organ physiology and pathophysiology. We have been developing new modeling methods and tools that fill gaps in our ability to bridge critical mesoscales such as the macromolecular (nm) to subcellular (pm) levels. Excellent progress has been made building structurally detailed 3-D models of subcellular architecture from electron tomographic image volumes and using these to simulate transport and signaling processes. But to span from molecular to whole cell, tissue and organ scales other approaches will also be needed. The present supplementary revision application proposes to develop new multi-scale modeling tools and methods that: (1) Allow Markov models (MM) of molecular states to be defined using molecular simulations including molecular dynamics (MD), and Brownian dynamics (BD) models;(2) Facilitate the inclusion of Markov models into systems models of cell signaling, electrophysiology and mechanics suitable for use in multiscale models of cell, tissue and organ biomechanics and biophysics. The goal of this competitive revision application is to develop new multiscale modeling tools and methods that will help bridge the gap between molecular models of individual sarcomeric protein components including actin, myosin and components of the troponin-tropomyosin regulatory complex and cellular models of whole sarcomere activation and mechanics in striated muscle. We also identify other applications ofthe proposed new tools including studies on the role of sarcomeric mutations in muscle diseases and on the function of protein kinase A.
Defects in the contraction of cardiac cells, or cardiomyopathies, are a hallmark of heart disease. Underlying these pathologies is the compromised performance of myofilaments, which are the key contractile components of myocytes. The new tools will enable scientists to elucidate important questions such as how seemingly disparate mutations on distinct protein complexes can result in similar phenotypes such as diseases in the heart or muscle and enable scientists to develop more effective therapies.
|Schilling, Jan M; Horikawa, Yousuke T; Zemljic-Harpf, Alice E et al. (2016) Electrophysiology and metabolism of caveolin-3-overexpressing mice. Basic Res Cardiol 111:28|
|Yang, Longhua; Skjevik, Ã…ge A; Han Du, Wen-Ge et al. (2016) Data for molecular dynamics simulations of B-type cytochrome c oxidase with the Amber force field. Data Brief 8:1209-14|
|Swift, Robert V; Jusoh, Siti A; Offutt, Tavina L et al. (2016) Knowledge-Based Methods To Train and Optimize Virtual Screening Ensembles. J Chem Inf Model 56:830-42|
|Goldgof, Gregory M; Durrant, Jacob D; Ottilie, Sabine et al. (2016) Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor. Sci Rep 6:27806|
|Yang, Longhua; Skjevik, Ã…ge A; Han Du, Wen-Ge et al. (2016) Water exit pathways and proton pumping mechanism in B-type cytochrome c oxidase from molecular dynamics simulations. Biochim Biophys Acta 1857:1594-606|
|Im, Wonpil; Liang, Jie; Olson, Arthur et al. (2016) Challenges in structural approaches to cell modeling. J Mol Biol 428:2943-64|
|Lee, Christopher T; Comer, Jeffrey; Herndon, Conner et al. (2016) Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds. J Chem Inf Model 56:721-33|
|Schiffer, Jamie M; Feher, Victoria A; Malmstrom, Robert D et al. (2016) Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A. Biophys J 111:1631-1640|
|Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A et al. (2016) Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention. Ann Biomed Eng 44:2642-60|
|Dewan, Sukriti; McCabe, Kimberly J; Regnier, Michael et al. (2016) Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation-An Integrated Multiscale Modeling Study. J Phys Chem B 120:8264-75|
Showing the most recent 10 out of 78 publications