Publications by authors named "Milo M Lin"

Neural circuits must balance plasticity and stability to enable continual learning without catastrophic forgetting, a pervasive feature of artificial neural networks trained using end-to-end learning (e.g. backpropagation).

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Neurotransmitter release is triggered in microseconds by Ca-binding to the Synaptotagmin-1 C-domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 CB domain to SNARE complexes through a "primary interface" comprising two regions (I and II). The Synaptotagmin-1 Ca-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers, or helping bridge the membranes, but SNARE complex binding through the primary interface orients the Ca-binding loops away from the fusion site, hindering these putative activities.

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Article Synopsis
  • Neurotransmitter release happens quickly through the interaction of calcium (Ca) with Synaptotagmin-1 and the formation of SNARE complexes, but how these interactions lead to membrane fusion is still unclear.
  • Synaptotagmin-1's Ca-binding loops were thought to help merge membranes, but new simulations show they might actually hinder SNARE function, contradicting older models.
  • Recent experiments suggest that when Ca binds to Synaptotagmin-1, it reorients the protein in a way that aids in bringing SNARE complexes together for membrane fusion, acting like a lever to enhance the process.
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Article Synopsis
  • SNARE proteins (syntaxin-1, SNAP-25, synaptobrevin) play a crucial role in rapidly releasing neurotransmitters by forming complexes that fuse synaptic vesicles with cell membranes within microseconds.* -
  • Current theories suggest that these proteins work mechanically like rods, zipping together to bring membranes closer, but the exact mechanism of fast fusion is still unclear.* -
  • Molecular dynamics simulations propose a new model where the zippering of SNARE helices initiates fusion at a local level, expanding hydrophobic regions to form fusion pores, and indicates that polyunsaturated lipids might enhance the efficiency of this process.*
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Protein fibril self-assembly is a universal transition implicated in neurodegenerative diseases. Although fibril structure/growth are well characterized, fibril nucleation is poorly understood. Here, we use a computational-experimental approach to resolve fibril nucleation.

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To automate the discovery of new scientific and engineering principles, artificial intelligence must distill explicit rules from experimental data. This has proven difficult because existing methods typically search through the enormous space of possible functions. Here we introduce deep distilling, a machine learning method that does not perform searches but instead learns from data using symbolic essence neural networks and then losslessly condenses the network parameters into a concise algorithm written in computer code.

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Allostery, the transfer of information between distant parts of a macromolecule, is a fundamental feature of protein function and regulation. However, allosteric mechanisms are usually not explained by protein structure, requiring information on correlated fluctuations uniquely accessible to molecular simulation. Existing work to extract allosteric pathways from molecular dynamics simulations has focused on thermodynamic correlations.

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Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) restricts human immunodeficiency virus type 1 (HIV-1) infection by reducing the intracellular dNTP pool. We have shown that SAMHD1 suppresses nuclear factor kappa-B activation and type I interferon (IFN-I) induction by viral infection and inflammatory stimuli. However, the mechanism by which SAMHD1 inhibits IFN-I remains unclear.

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Proteins can aggregate into disordered aggregates or ordered assemblies such as amyloid fibrils. These two distinct phases serve differing roles in function and disease. How protein sequence determines the preferred phase is unknown.

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Article Synopsis
  • * The exact processes leading to membrane fusion are still not fully understood, partly due to the challenges of studying these dynamic interactions experimentally.
  • * Molecular dynamics simulations indicate that while SNARE proteins promote initial membrane contact, the primed state—featuring Synaptotagmin-1 and complexin-1—prevents premature fusion while remaining primed for quick release when calcium levels rise.
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The success of deep neural networks suggests that cognition may emerge from indecipherable patterns of distributed neural activity. Yet these networks are pattern-matching black boxes that cannot simulate higher cognitive functions and lack numerous neurobiological features. Accordingly, they are currently insufficient computational models for understanding neural information processing.

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To control viral infection, vertebrates rely on both inducible interferon responses and less well-characterized cell-intrinsic responses composed of "at the ready" antiviral effector proteins. Here, we show that E3 ubiquitin ligase TRIM7 is a cell-intrinsic antiviral effector that restricts multiple human enteroviruses by targeting viral 2BC, a membrane remodeling protein, for ubiquitination and proteasome-dependent degradation. Selective pressure exerted by TRIM7 results in emergence of a TRIM7-resistant coxsackievirus with a single point mutation in the viral 2C ATPase/helicase.

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Predicting the behavior of heterogeneous nonequilibrium systems is currently analytically intractable. Consequently, complex biological systems have resisted unifying principles. Here, I introduce a mapping from dynamical systems to battery-resistor circuits.

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Cofilin and ADF are cytoskeleton remodeling proteins that cooperatively bind and fragment actin filaments. Bound cofilin molecules do not directly interact with each other, indicating that cooperative binding of cofilin is mediated by the actin filament lattice. Cofilactin is therefore a model system for studying allosteric regulation of self-assembly.

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T cells can be controllably stimulated through antigen-specific or nonspecific protocols. Accompanying functional hallmarks of T cell activation can include cytoskeletal reorganization, cell size increase, and cytokine secretion. Photon-induced near-field electron microscopy (PINEM) is used to image and quantify evanescent electric fields at the surface of T cells as a function of various stimulation conditions.

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Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within tau's repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as VQIVYK.

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How protein structure encodes functionality is not fully understood. For example, long-range intraprotein communication can occur without measurable conformational change and is often not captured by existing structural correlation functions. It is shown here that important functional information is encoded in the timing of protein motions, rather than motion itself.

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Cooperative interactions are widespread in biochemical networks, providing the nonlinear response that underlies behavior such as ultrasensitivity and robust switching. We introduce a temporal correlation function-the conditional activity-to study the behavior of these phenomena. Applying it to the bistable genetic switch in bacteriophage lambda, we find that cooperative binding between binding sites on the prophage DNA lead to non-Markovian behavior, as quantified by the conditional activity.

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Helices are the "hydrogen atoms" of biomolecular complexity; the DNA/RNA double hairpin and protein α-helix ubiquitously form the building blocks of life's constituents at the nanometer scale. Nevertheless, the formation processes of these structures, especially the dynamical pathways and rates, remain challenging to predict and control. Here, we present a general analytical method for constructing dynamical free-energy landscapes of helices.

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To find the native conformation (fold), proteins sample a subspace that is typically hundreds of orders of magnitude smaller than their full conformational space. Whether such fast folding is intrinsic or the result of natural selection, and what is the longest foldable protein, are open questions. Here, we derive the average conformational degeneracy of a lattice polypeptide chain in water and quantitatively show that the constraints associated with hydrophobic forces are themselves sufficient to reduce the effective conformational space to a size compatible with the folding of proteins up to approximately 200 amino acids long within a biologically reasonable amount of time.

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Among the macromolecular patterns of biological significance, right-handed α-helices are perhaps the most abundant structural motifs. Here, guided by experimental findings, we discuss both ultrafast initial steps and longer-time-scale structural dynamics of helix-coil transitions induced by a range of temperature jumps in large, isolated macromolecular ensembles of an α-helical protein segment thymosin β(9) (Tβ(9)), and elucidate the comprehensive picture of (un)folding. In continuation of an earlier theoretical work from this laboratory that utilized a simplistic structure-scrambling algorithm combined with a variety of self-avoidance thresholds to approximately model helix-coil transitions in Tβ(9), in the present contribution we focus on the actual dynamics of unfolding as obtained from massively distributed ensemble-convergent MD simulations which provide an unprecedented scope of information on the nature of transient macromolecular structures, and with atomic-scale spatiotemporal resolution.

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As the simplest and most prevalent motif of protein folding, α-helix initiation is the starting point of macromolecular complexity. In this work, helix initiation was directly measured via ultrafast temperature-jump spectroscopy on the smallest possible helix nucleus for which only the first turn is formed. The rate's dependence on sequence, length, and temperature reveals the fastest possible events in protein folding dynamics, and it was possible to separate the rate-limiting torsional (conformational) diffusion from the fast annealing of the helix.

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Of special interest in molecular biology is the study of structural and conformational changes which are free of the additional effects of the environment. In the present contribution, we report on the ultrafast unfolding dynamics of a large DNA macromolecular ensemble in vacuo for a number of temperature jumps, and make a comparison with the unfolding dynamics of the DNA in aqueous solution. A number of coarse-graining approaches, such as kinetic intermediate structure (KIS) model and ensemble-averaged radial distribution functions, are used to account for the transitional dynamics of the DNA without sacrificing the structural resolution.

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Protein structural integrity and flexibility are intimately tied to solvation. Here, we examine the effect that changes in bulk and local solvent properties have on protein structure and stability. We observe the change in solvation of an unfolding of the protein model, melittin, in the presence of a denaturant, trifluoroethanol.

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