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Computational Research in Molecular Chemistry
An Open Source Mesh Generation Platform for Biophysical Modeling Using Realistic Cellular GeometriesLee, C.T., J.G. Laughlin, N.A. de La Beaumelle, R.E. Amaro, J.A. McCammon, R. Ramamoorthi, M.J. Holst, P. Rangamani.Biophys. J. 118, 1003–1008 (2020).    
Advances in imaging methods such as electron microscopy, tomography, and other modalities are enabling high-resolution reconstructions of cellular and organelle geometries. Such advances pave the way for using these geometries for biophysical and mathematical modeling once these data can be represented as a geometric mesh, which, when carefully conditioned, enables the discretization and solution of partial differential equations. In this study, we outline the steps for a naïve user to approach GAMer 2, a mesh generation code written in C++ designed to convert structural datasets to realistic geometric meshes, while preserving the underlying shapes. We present two example cases, 1) mesh generation at the subcellular scale as informed by electron tomography, and 2) meshing a protein with structure from x-ray crystallography. We further demonstrate that the meshes generated by GAMer are suitable for use with numerical methods. Together, this collection of libraries and tools simplifies the process of constructing realistic geometric meshes from structural biology data.
Gating Mechanism of Elongating β-Ketoacyl-ACP SynthasesMindrebo, J.T., A. Patel, W.E. Kim, A. Chen, T.G. Bartholow, T.D. Davis, J.J. La Clair, J.A. McCammon, J.P. Noel, M.D. Burkart.Nature Commun. 11, Article number: 1727 (2020)    
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3D mesh processing using GAMer 2 to enable reaction-diffusion simulations in realistic cellular geometriesLee, C.T., J. G. Laughlin, N. A. de La Beaumelle, R. E. Amaro, J. A. McCammon, R. Ramamoorthi, M. J. Holst, P. Rangamani.PLOS Comp. Biol. 16, e1007756 (2020)    
Recent advances in electron microscopy have enabled the imaging of single cells in 3D at nanometer length scale resolutions. An uncharted frontier for in silico biology is the ability to simulate cellular processes using these observed geometries. Enabling such simulations requires watertight meshing of electron micrograph images into 3D volume meshes, which can then form the basis of computer simulations of such processes using numerical techniques such as the Finite Element Method (FEM). In this paper, we describe the use of our recently rewritten mesh processing software, GAMer 2, to bridge the gap between poorly conditioned meshes generated from segmented micrographs and boundary marked tetrahedral meshes which are compatible with simulation. We demonstrate the application of a workflow using GAMer 2 to a series of electron micrographs of neuronal dendrite morphology explored at three different length scales and show that the resulting meshes are suitable for finite element simulations. This work is an important step towards making physical simulations of biological processes in realistic geometries routine. Innovations in algorithms to reconstruct and simulate cellular length scale phenomena based on emerging structural data will enable realistic physical models and advance discovery at the interface of geometry and cellular processes. We posit that a new frontier at the intersection of computational technologies and single cell biology is now open.
Interfacial Plasticity Facilitates High Reaction Rate of E. coli FAS Malonyl-CoA:ACP TransacylaseMisson, L.E., J.T. Mindrebo, T.D. Davis, A. Patel, J.A. McCammon, J.P. Noel, M.D. Burkart.Proc. Natl. Acad. Sci. USA 117, 24224-24233 (2020).    
Fatty acid synthases (FASs) and polyketide synthases (PKSs) iteratively elongate and often reduce two-carbon ketide units in de novo fatty acid and polyketide biosynthesis. Cycles of chain extensions in FAS and PKS are initiated by an acyltransferase (AT), which loads monomer units onto acyl carrier proteins (ACPs), small, flexible proteins that shuttle covalently linked intermediates between catalytic partners. Formation of productive ACP-AT interactions is required for catalysis and specificity within primary and secondary FAS and PKS pathways. Here, we use the Escherichia coli FAS AT, FabD, and its cognate ACP, AcpP, to interrogate type II FAS ACP-AT interactions. We utilize a covalent crosslinking probe to trap transient interactions between AcpP and FabD to elucidate the X-ray crystal structure of a type II ACP-AT complex. Our structural data are supported using a combination of mutational, crosslinking, and kinetic analyses, and long-timescale molecular dynamics (MD) simulations. Together, these complementary approaches reveal key catalytic features of FAS ACP-AT interactions. These mechanistic inferences suggest that AcpP adopts multiple, productive conformations at the AT binding interface, allowing the complex to sustain high transacylation rates. Furthermore, MD simulations support rigid body subdomain motions within the FabD structure that may play a key role in AT activity and substrate selectivity.
Predicting the effects of dATP on cardiac contraction using multiscale modeling of the sarcomere. Archives of Biochemistry and BiophysicsMcCabe, K.J., Aboelkassem, Y., Teitgen, A.E., Huber, G.A., McCammon, J.A., Regnier, M., McCulloch, A.D.Archives of Biochemistry and Biophysics, Volume 695, 30 November 108582 (2020)    
2'-deoxy-ATP (dATP) is a naturally occurring small molecule that has shown promise as a therapeutic because it significantly increases cardiac myocyte force development even at low dATP/ATP ratios. To investigate mechanisms by which dATP alters myosin crossbridge dynamics, we used Brownian dynamics simulations to calculate association rates between actin and ADP- or dADP-bound myosin. These rates were then directly incorporated in a mechanistic Monte Carlo Markov Chain model of cooperative sarcomere contraction. A unique combination of increased powerstroke and detachment rates was required to match experimental steady-state and kinetic data for dATP force production in rat cardiac myocytes when the myosin attachment rate in the model was constrained by the results of a Brownian dynamics simulation. Nearest-neighbor cooperativity was seen to contribute to, but not fully explain, the steep relationship between dATP/ATP ratio and steady-state force-development observed at lower dATP concentrations. Dynamic twitch simulations performed using measured calcium transients as inputs showed that the effects of dATP on the crossbridge alone were not sufficient to explain experimentally observed enhancement of relaxation kinetics by dATP treatment. Hence, dATP may also affect calcium handling even at low concentrations. By enabling the effects of dATP on sarcomere mechanics to be predicted, this multi-scale modeling framework may elucidate the molecular mechanisms by which dATP can have therapeutic effects on cardiac contractile dysfunction
Multiscale simulations examining glycan shield effects on drug binding to influenza neuraminidase.Seitz, C., L. Casalino, R. Konecny, G. Huber, R. E. Amaro, J. A. McCammon.Biophys. J., Vol. 119, Issue 11, 2275-2289 (2020)    
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