Browsing by Subject "computational modeling"

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    Accelerated computation of free energy profile at ab initio quantum mechanical/molecular mechanical accuracy via a semi-empirical reference potential. II. Recalibrating semi-empirical parameters with force matching
    (The Royal Society of Chemistry, 2019-08-15) Pan, Xiaoliang; Li, Pengfei; Ho, Junming; Pu, Jingzhi; Mei, Ye; Shao, Yihan; Chemistry and Chemical Biology, School of Science
    An efficient and accurate reference potential simulation protocol is proposed for producing ab initio quantum mechanical molecular mechanical (AI-QM/MM) quality free energy profiles for chemical reactions in a solvent or macromolecular environment. This protocol involves three stages: (a) using force matching to recalibrate a semi-empirical quantum mechanical (SE-QM) Hamiltonian for the specific reaction under study; (b) employing the recalibrated SE-QM Hamiltonian (in combination with molecular mechanical force fields) as the reference potential to drive umbrella samplings along the reaction pathway; and (c) computing AI-QM/MM energy values for collected configurations from the sampling and performing weighted thermodynamic perturbation to acquire AI-QM/MM corrected reaction free energy profile. For three model reactions (identity SN2 reaction, Menshutkin reaction, and glycine proton transfer reaction) in aqueous solution and one enzyme reaction (Claisen arrangement in chorismate mutase), our simulations using recalibrated PM3 SE-QM Hamiltonians well reproduced QM/MM free energy profiles at the B3LYP/6–31G* level of theory all within 1 kcal/mol with a 20 to 45 fold reduction in the computer time.
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    Dynamical ventral tegmental area circuit mechanisms of alcohol‐dependent dopamine release
    (Wiley, 2019) di Volo, Matteo; Morozova, Ekaterina O.; Lapish, Christopher C.; Kuznetsov, Alexey; Gutkin, Boris; Psychology, School of Science
    A large body of data has identified numerous molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms interact to result in dysregulated dopamine (DA) release under the influence of alcohol in vivo remains unclear. In this manuscript, we delineate potential circuit‐level mechanisms responsible for EtOH‐dependent dysregulation of DA release from the ventral tegmental area (VTA) into its projection areas. For this purpose, we constructed a circuit model of the VTA that integrates realistic Glutamatergic (Glu) inputs and reproduces DA release observed experimentally. We modelled the concentration‐dependent effects of EtOH on its principal VTA targets. We calibrated the model to reproduce the inverted U‐shape dose dependence of DA neuron activity on EtOH concentration. The model suggests a primary role of EtOH‐induced boost in the Ih and AMPA currents in the DA firing‐rate/bursting increase. This is counteracted by potentiated GABA transmission that decreases DA neuron activity at higher EtOH concentrations. Thus, the model connects well‐established in vitro pharmacological EtOH targets with its in vivo influence on neuronal activity. Furthermore, we predict that increases in VTA activity produced by moderate EtOH doses require partial synchrony and relatively low rates of the Glu afferents. We propose that the increased frequency of transient (phasic) DA peaks evoked by EtOH results from synchronous population bursts in VTA DA neurons. Our model predicts that the impact of acute ETOH on dopamine release is critically shaped by the structure of the cortical inputs to the VTA.
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    New Probabilistic Multi-graph Decomposition Model to Identify Consistent Human Brain Network Modules
    (IEEE, 2016-12) Luo, Dijun; Huo, Zhouyuan; Wang, Yang; Saykin, Andrew J.; Shen, Li; Huang, Heng; Radiology and Imaging Sciences, School of Medicine
    Many recent scientific efforts have been devoted to constructing the human connectome using Diffusion Tensor Imaging (DTI) data for understanding large-scale brain networks that underlie higher-level cognition in human. However, suitable network analysis computational tools are still lacking in human brain connectivity research. To address this problem, we propose a novel probabilistic multi-graph decomposition model to identify consistent network modules from the brain connectivity networks of the studied subjects. At first, we propose a new probabilistic graph decomposition model to address the high computational complexity issue in existing stochastic block models. After that, we further extend our new probabilistic graph decomposition model for multiple networks/graphs to identify the shared modules cross multiple brain networks by simultaneously incorporating multiple networks and predicting the hidden block state variables. We also derive an efficient optimization algorithm to solve the proposed objective and estimate the model parameters. We validate our method by analyzing both the weighted fiber connectivity networks constructed from DTI images and the standard human face image clustering benchmark data sets. The promising empirical results demonstrate the superior performance of our proposed method.