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Digital contact tracing plays a crucial role in alleviating an outbreak, and designing multilevel digital contact tracing for a country is an open problem due to the analysis of large volumes of temporal contact data. We develop a multilevel digital contact tracing framework that constructs dynamic contact graphs from the proximity contact data. Prominently, we introduce the edge label of the contact graph as a binary circular contact queue, which holds the temporal social interactions during the incubation period. After that, our algorithm prepares the direct and indirect (multilevel) contact list for a given set of infected persons from the contact graph. Finally, the algorithm constructs the infection pathways for the trace list. We implement the framework and validate the contact tracing process with synthetic and real-world data sets. In addition, analysis reveals that for COVID-19 close contact parameters, the framework takes reasonable space and time to create the infection pathways. Our framework can apply to any epidemic spreading by changing the algorithm's parameters., Comment: 21 Pages, 14 Figures with Appendix

We investigate the role of order/disorder transitions in alchemical simulations of protein-ligand absolute binding free energies. We show, in the context of a potential of mean force description, that for a benchmarking system (the complex between the L99A mutant of T4 lysozyme and 3-iodotoluene) and for a more challenging system relevant for medicinal applications (the complex of the farnesoid X receptor and inhibitor 26 from a recent D3R challenge) that order/disorder transitions can significantly hamper Hamiltonian replica exchange sampling efficiency and slow down the rate of equilibration of binding free energy estimates. We further show that our analytical model of alchemical binding combined with the formalism developed by Straub et al. for the treatment of order/disorder transitions of molecular systems can be successfully employed to analyze the transitions and help design alchemical schedules and soft-core functions that avoid or reduce the adverse effects of rare binding/unbinding transitions. The results of this work pave the way for the application of these techniques to the alchemical estimation with explicit solvation of hydration free energies and absolute binding free energies of systems undergoing order/disorder transitions.

Confined hydration and conformational flexibility are some of the challenges encountered for the rational design of selective antagonists of G-protein coupled receptors. We present a set of C3-substituted (-)-stepholidine derivatives as potent binders of the dopamine D3 receptor. The compounds are characterized biochemically, as well as by computer modeling using a novel molecular dynamics-based alchemical binding free energy approach which incorporates the effect of the displacement of enclosed water molecules from the binding site. The free energy of displacement of specific hydration sites is obtained using the Hydration Site Analysis method with explicit solvation. This work underscores the critical role of confined hydration and conformational reorganization in the molecular recognition mechanism of dopamine receptors and illustrates the potential of binding free energy models to represent these key phenomena., Comment: This is the first report of using enclosed hydration in estimating binding free energies of protein-ligand complexes using implicit solvation