Publications

Molecular docking, which aims to find the most stable interacting configuration of a set of molecules, is of critical importance to drug discovery. Although a considerable number of classical algorithms have been developed to carry out molecular docking, most focus on the limiting case of docking two molecules. Since the number of possible configurations of N molecules is exponential in N, those exceptions which permit docking of more than two molecules scale poorly, requiring exponential resources to find high-quality solutions. Here, we introduce a one-hot encoded quadratic unconstrained binary optimization formulation (QUBO) of the multibody molecular docking problem, which is suitable for solution by quantum annealer. Our approach involves a classical pre-computation of pairwise interactions, which scales only quadratically in the number of bodies while permitting well-vetted scoring functions like the Rosetta REF2015 energy function to be used. In a second step, we use the quantum annealer to sample low-energy docked configurations efficiently, considering all possible docked configurations simultaneously through quantum superposition. We show that we are able to minimize the time needed to find diverse low-energy docked configurations by tuning the strength of the penalty used to enforce the one-hot encoding, demonstrating a 3-4 fold improvement in solution quality and diversity over performance achieved with conventional penalty strengths. By mapping the configurational search to a form compatible with current- and future-generation quantum annealers, this work provides an alternative means of solving multibody docking problems that may prove to have performance advantages for large problems, potentially circumventing the exponential scaling of classical approaches and permitting a much more efficient solution to a problem central to drug discovery and validation pipelines.

The cell nucleus is enveloped by a complex membrane, whose wrinkling has been implicated in disease and cellular aging. The biophysical dynamics and spectral evolution of nuclear wrinkling during multicellular development remain poorly understood due to a lack of direct quantitative measurements. Here, we combine live-imaging experiments, theory, and simulations to characterize the onset and dynamics of nuclear wrinkling during egg development in the fruit fly, Drosophila melanogaster, when nurse cell nuclei increase in size and display stereotypical wrinkling behavior. A spectral analysis of three-dimensional high-resolution data from several hundred nuclei reveals a robust asymptotic power-law scaling of angular fluctuations consistent with renormalization and scaling predictions from a nonlinear elastic shell model. We further demonstrate that nuclear wrinkling can be reversed through osmotic shock and suppressed by microtubule disruption, providing tunable physical and biological control parameters for probing mechanical properties of the nuclear envelope. Our findings advance the biophysical understanding of nuclear membrane fluctuations during early multicellular development.

Peptides are commonly used as therapeutic agents. However, they suffer from easy degradation and instability. Replacing natural by non-natural amino acids can avoid these problems, and potentially improve the affinity towards the target protein. Here, we present a computational pipeline to optimize peptides based on adding non-natural amino acids while improving their binding affinity. The workflow is an iterative computational evolution algorithm, inspired by the PARCE protocol, that performs single-point mutations on the peptide sequence using modules from the Rosetta framework. The modifications can be guided based on the structural properties or previous knowledge of the biological system. At each mutation step, the affinity to the protein is estimated by sampling the complex conformations and applying a consensus metric using various open protein-ligand scoring functions. The mutations are accepted based on the score differences, allowing for an iterative optimization of the initial peptide. The sampling/scoring scheme was benchmarked with a set of protein-peptide complexes where experimental affinity values have been reported. In addition, a basic application using a known protein-peptide complex is also provided. The structure- and dynamic-based approach allows users to optimize bound peptides, with the option to personalize the code for further applications. The protocol, called mPARCE, is available at: https://github.com/rochoa85/mPARCE/.

How does breaking the symmetry of an equation alter the symmetry of its solutions? Here, we systematically examine how reducing underlying symmetries from spherical to axisymmetric influences the dynamics of an archetypal model of cell polarization, a key process of biological spatial self-organization. Cell polarization is characterized by nonlinear and non-local dynamics, but we overcome the theory challenges these traits pose by introducing a broadly applicable numerical scheme allowing us to efficiently study continuum models in a wide range of geometries. Guided by numerical results, we discover a dynamical hierarchy of timescales that allows us to reduce relaxation to a purely geometric problem of area-preserving geodesic curvature flow. Through application of variational results, we analytically construct steady states on a number of biologically relevant shapes. In doing so, we reveal non-trivial solutions for symmetry breaking.

We report observations of the recently discovered warm Neptune TOI-674 b (5.25 \rearth{}, 23.6 \mearth{}) with the Hubble Space Telescope's Wide Field Camera 3 instrument. TOI-674 b is in the Neptune desert, an observed paucity of Neptune-size exoplanets at short orbital periods. Planets in the desert are thought to have complex evolutionary histories due to photoevaporative mass loss or orbital migration, making identifying the constituents of their atmospheres critical to understanding their origins. We obtained near-infrared transmission spectroscopy of the planet's atmosphere with the G141 grism. After extracting, detrending, and fitting the spectral lightcurves to measure the planet's transmission spectrum, we used the petitRADTRANS atmospheric spectral synthesis code to perform retrievals on the planet's atmosphere to identify which absorbers are present. These results show moderate evidence for increased absorption at 1.4 μm due to water vapor at 2.9σ (Bayes factor = 15.8), as well as weak evidence for the presence of clouds at 2.2σ (Bayes factor = 4.0). TOI-674 b is a strong candidate for further study to refine the water abundance, which is poorly constrained by our data. We also incorporated new TESS short-cadence optical photometry, as well as Spitzer/IRAC data, and re-fit the transit parameters for the planet. We find the planet to have the following transit parameters: Rp/R∗=0.1135±0.0006, T0=2458544.523792±0.000452 BJD, and P=1.977198±0.00007 d. These measurements refine the planet radius estimate and improve the orbital ephemerides for future transit spectroscopy observations of this highly intriguing warm Neptune.

We develop a rapid algorithm for the evolution of stable, circular, circumbinary discs suitable for parameter estimation and population synthesis modelling. Our model includes disc mass and angular momentum changes, accretion on to the binary stars, and binary orbital eccentricity pumping. We fit our model to the post-asymptotic giant branch (post-AGB) circumbinary disc around IRAS 08544−4431, finding reasonable agreement despite the simplicity of our model. Our best-fitting disc has a mass of about 0.01M⊙ and angular momentum 2.7×1052gcm2s−1≃9M⊙kms−1au⁠, corresponding to 0.0079 and 0.16 of the common-envelope mass and angular momentum, respectively. The best-fitting disc viscosity is αdisc = 5 × 10−3 and our tidal torque algorithm can be constrained such that the inner edge of the disc Rin ∼ 2a. The inner binary eccentricity reaches about 0.13 in our best-fitting model of IRAS 08544−4431, short of the observed 0.22. The circumbinary disc evaporates quickly when the post-AGB star reaches a temperature of ∼6×104K⁠, suggesting that planetismals must form in the disc in about 104yr if secondary planet formation is to occur, while accretion from the disc on to the stars at ∼10 times the inner-edge viscous rate can double the disc lifetime.

We build a multi-output generative model for quasar spectra and the properties of their black hole engines, based on a Gaussian process latent-variable model. This model treats every quasar as a vector of latent properties such that the spectrum and all physical properties of the quasar are associated with non-linear functions of those latent parameters; the Gaussian process kernel functions define priors on the function space. Our generative model is trained with a justifiable likelihood function that allows us to treat heteroscedastic noise and missing data correctly, which is crucial for all astrophysical applications. It can simultaneously predict unobserved spectral regions and the physical properties of quasars in held-out test data. We apply the model to rest-frame ultraviolet and optical quasar spectra for which precise black hole masses (based on reverberation-mapping measurements) are available. Unlike reverberation-mapping studies that require multi-epoch data, our model predicts black hole masses from single-epoch spectra—even with limited spectral coverage. We demonstrate the capabilities of the model by predicting black hole masses and unobserved spectral regions. We find that we predict black hole masses at close to the best possible accuracy.

We present late-time radio/millimeter (as well as optical/UV and X-ray) detections of the tidal disruption event (TDE) AT2018hyz, spanning 970−1300 d after optical discovery. In conjunction with earlier deeper limits, including at ≈700 d, our observations reveal rapidly rising emission at 0.8−240 GHz, steeper than Fν∝t5 relative to the time of optical discovery. Such a steep rise cannot be explained in any reasonable scenario of an outflow launched at the time of disruption (e.g., off-axis jet, sudden increase in the ambient density), and instead points to a delayed launch. Our multi-frequency data allow us to directly determine the radius and energy of the radio-emitting outflow, showing that it was launched ≈750 d after optical discovery. The outflow velocity is mildly relativistic, with β≈0.25 and ≈0.6 for a spherical and a 10∘ jet geometry, respectively, and the minimum kinetic energy is EK≈5.8×1049 and ≈6.3×1049 erg, respectively. This is the first definitive evidence for the production of a delayed mildly-relativistic outflow in a TDE; a comparison to the recently-published radio light curve of ASASSN-15oi suggests that the final re-brightening observed in that event (at a single frequency and time) may be due to a similar outflow with a comparable velocity and energy. Finally, we note that the energy and velocity of the delayed outflow in AT2018hyz are intermediate between those of past non-relativistic TDEs (e.g., ASASSN-14li, AT2019dsg) and the relativistic TDE Sw\,J1644+57. We suggest that such delayed outflows may be common in TDEs.

In fluid dynamics, constitutive models are often used to describe the unresolved turbulence and to close the Reynolds averaged Navier–Stokes (RANS) equations. Traditional PDE-based constitutive models are usually too rigid to calibrate with a large set of high-fidelity data. Moreover, commonly used turbulence models are based on the weak equilibrium assumption, which cannot adequately capture the nonlocal physics of turbulence. In this work, we propose using a vector-cloud neural network (VCNN) to learn the nonlocal constitutive model, which maps a regional mean flow field to the local turbulence quantities without solving the transport PDEs. The network is strictly invariant to coordinate translation, rotation, and uniform motion, as well as ordering of the input points. The VCNN-based nonlocal constitutive model is trained and evaluated on flows over a family of parameterized periodic hills. Numerical results demonstrate its predictive capability on target turbulence quantities of turbulent kinetic energy k and dissipation ɛ. More importantly, we investigate the robustness and stability of the method by coupling the trained model back to RANS solver. The solver shows good convergence with the simulated velocity field comparable to that based on k–ɛ model when starting from a reasonable initial condition. This study, as a proof of concept, highlights the feasibility of using a nonlocal, frame-independent, neural network-based constitutive model to close the RANS equations, paving the way for the further emulation of the Reynolds stress transport models.

Self-supervised learning (SSL) is currently one of the premier techniques to create data representations that are actionable for transfer learning in the absence of human annotations. Despite their success, the underlying geometry of these representations remains elusive, which obfuscates the quest for more robust, trustworthy, and interpretable models. In particular, mainstream SSL techniques rely on a specific deep neural network architecture with two cascaded neural networks: the encoder and the projector. When used for transfer learning, the projector is discarded since empirical results show that its representation generalizes more poorly than the encoder's. In this paper, we investigate this curious phenomenon and analyze how the strength of the data augmentation policies affects the data embedding. We discover a non-trivial relation between the encoder, the projector, and the data augmentation strength: with increasingly larger augmentation policies, the projector, rather than the encoder, is more strongly driven to become invariant to the augmentations. It does so by eliminating crucial information about the data by learning to project it into a low-dimensional space, a noisy estimate of the data manifold tangent plane in the encoder representation. This analysis is substantiated through a geometrical perspective with theoretical and empirical results.