Subdiffusion and Many-Body Quantum Chaos with Kinetic Constraints.

We investigate the spectral and transport properties of many-body quantum systems with conserved charges and kinetic constraints. Using random unitary circuits, we compute ensemble-averaged spectral form factors and linear-response correlation functions, and find that their characteristic timescales are given by the inverse gap of an effective Hamiltonian-or equivalently, a transfer matrix describing a classical Markov process. Our approach allows us to connect directly the Thouless time, t_{Th}, determined by the spectral form factor, to transport properties and linear-response correlators. Using tensor network methods, we determine the dynamical exponent z for a number of constrained, conserving models. We find universality classes with diffusive, subdiffusive, quasilocalized, and localized dynamics, depending on the severity of the constraints. In particular, we show that quantum systems with "Fredkin" constraints exhibit anomalous transport with dynamical exponent z≃8/3.

Spectral Statistics and Many-Body Quantum Chaos with Conserved Charge.

We investigate spectral statistics in spatially extended, chaotic many-body quantum systems with a conserved charge. We compute the spectral form factor K(t) analytically for a minimal Floquet circuit model that has a U(1) symmetry encoded via spin-1/2 degrees of freedom. Averaging over an ensemble of realizations, we relate K(t) to a partition function for the spins, given by a Trotterization of the spin-1/2 Heisenberg ferromagnet. Using Bethe ansatz techniques, we extract the "Thouless time" t_{Th} demarcating the extent of random matrix behavior, and find scaling behavior governed by diffusion for K(t) at t≲t_{Th}. We also report numerical results for K(t) in a generic Floquet spin model, which are consistent with these analytic predictions.

Integrable Many-Body Quantum Floquet-Thouless Pumps.

We construct an interacting integrable Floquet model featuring quasiparticle excitations with topologically nontrivial chiral dispersion. This model is a fully quantum generalization of an integrable classical cellular automaton. We write down and solve the Bethe equations for the generalized quantum model and show that these take on a particularly simple form that allows for an exact solution: essentially, the quasiparticles behave like interacting hard rods. The generalized thermodynamics and hydrodynamics of this model follow directly, providing an exact description of interacting chiral particles in the thermodynamic limit. Although the model is interacting, its unusually simple structure allows us to construct operators that spread with no butterfly effect; this construction does not seem possible in other interacting integrable systems. This model exemplifies a new class of exactly solvable, interacting quantum systems specific to the Floquet setting.

The marine cyanobacterial metabolite gallinamide A is a potent and selective inhibitor of human cathepsin L.

A number of marine natural products are potent inhibitors of proteases, an important drug target class in human diseases. Hence, marine cyanobacterial extracts were assessed for inhibitory activity to human cathepsin L. Herein, we have shown that gallinamide A potently and selectively inhibits the human cysteine protease cathepsin L. With 30 min of preincubation, gallinamide A displayed an IC50 of 5.0 nM, and kinetic analysis demonstrated an inhibition constant of ki = 9000 ± 260 M(-1) s(-1). Preincubation-dilution and activity-probe experiments revealed an irreversible mode of inhibition, and comparative IC50 values display a 28- to 320-fold greater selectivity toward cathepsin L than closely related human cysteine cathepsin V or B. Molecular docking and molecular dynamics simulations were used to determine the pose of gallinamide in the active site of cathepsin L. These data resulted in the identification of a pose characterized by high stability, a consistent hydrogen bond network, and the reactive Michael acceptor enamide of gallinamide A positioned near the active site cysteine of the protease, leading to a proposed mechanism of covalent inhibition. These data reveal and characterize the novel activity of gallinamide A as a potent inhibitor of human cathepsin L.

Comparing neural-network scoring functions and the state of the art: applications to common library screening.

We compare established docking programs, AutoDock Vina and Schrödinger's Glide, to the recently published NNScore scoring functions. As expected, the best protocol to use in a virtual-screening project is highly dependent on the target receptor being studied. However, the mean screening performance obtained when candidate ligands are docked with Vina and rescored with NNScore 1.0 is not statistically different than the mean performance obtained when docking and scoring with Glide. We further demonstrate that the Vina and NNScore docking scores both correlate with chemical properties like small-molecule size and polarizability. Compensating for these potential biases leads to improvements in virtual screen performance. Composite NNScore-based scoring functions suited to a specific receptor further improve performance. We are hopeful that the current study will prove useful for those interested in computer-aided drug design.

The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase: a drug target for African sleeping sickness.

During the past century, several epidemics of human African trypanosomiasis, a deadly disease caused by the protist Trypanosoma brucei, have afflicted sub-Saharan Africa. Over 10 000 new victims are reported each year, with hundreds of thousands more at risk. As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed. The T. brucei galactose synthesis pathway is one potential therapeutic target. Although galactose is essential for T. brucei survival, the parasite lacks the transporters required to intake galactose from the environment. UDP-galactose 4'-epimerase (TbGalE) is responsible for the epimerization of UDP-glucose to UDP-galactose and is therefore of great interest to medicinal chemists. Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insights into TbGalE function and may help guide future computer-aided drug discovery efforts targeting this protein.

CrystalDock: a novel approach to fragment-based drug design.

We present a novel algorithm called CrystalDock that analyzes a molecular pocket of interest and identifies potential binding fragments. The program first identifies groups of pocket-lining receptor residues (i.e., microenvironments) and then searches for geometrically similar microenvironments present in publically available databases of ligand-bound experimental structures. Germane fragments from the crystallographic or NMR ligands are subsequently placed within the novel binding pocket. These positioned fragments can be linked together to produce ligands that are likely to be potent; alternatively, they can be joined to an inhibitor with a known or suspected binding pose to potentially improve binding affinity. To demonstrate the utility of the algorithm, CrystalDock is used to analyze the principal binding pockets of influenza neuraminidase and Trypanosoma brucei RNA editing ligase 1, validated drug targets in the fight against pandemic influenza and African sleeping sickness, respectively. In both cases, CrystalDock suggests modifications to known inhibitors that may improve binding affinity.

Engineered human skin substitutes undergo large-scale genomic reprogramming and normal skin-like maturation after transplantation to athymic mice.

Bioengineered skin substitutes can facilitate wound closure in severely burned patients, but deficiencies limit their outcomes compared with native skin autografts. To identify gene programs associated with their in vivo capabilities and limitations, we extended previous gene expression profile analyses to now compare engineered skin after in vivo grafting with both in vitro maturation and normal human skin. Cultured skin substitutes were grafted on full-thickness wounds in athymic mice, and biopsy samples for microarray analyses were collected at multiple in vitro and in vivo time points. Over 10,000 transcripts exhibited large-scale expression pattern differences during in vitro and in vivo maturation. Using hierarchical clustering, 11 different expression profile clusters were partitioned on the basis of differential sample type and temporal stage-specific activation or repression. Analyses show that the wound environment exerts a massive influence on gene expression in skin substitutes. For example, in vivo-healed skin substitutes gained the expression of many native skin-expressed genes, including those associated with epidermal barrier and multiple categories of cell-cell and cell-basement membrane adhesion. In contrast, immunological, trichogenic, and endothelial gene programs were largely lacking. These analyses suggest important areas for guiding further improvement of engineered skin for both increased homology with native skin and enhanced wound healing.