Richard W. Shuai

Deconvolution can be used to obtain sharp images or volumes from blurry or encoded measurements in imaging systems. Given knowledge of the system’s point spread function (PSF) over the field of view, a reconstruction algorithm can be used to recover a clear image or volume. Most deconvolution algorithms assume shift-invariance; however, in realistic systems, the PSF varies laterally and axially across the field of view due to aberrations or design. Shift-varying models can be used, but are often slow and computationally intensive. In this work, we propose a deep-learning-based approach that leverages knowledge about the system’s spatially varying PSFs for fast 2D and 3D reconstructions. Our approach, termed MultiWienerNet, uses multiple differentiable Wiener filters paired with a convolutional neural network to incorporate spatial variance. Trained using simulated data and tested on experimental data, our approach offers a <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"> <mml:mn>625</mml:mn> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mo>−</mml:mo> </mml:mrow> <mml:mn>1600</mml:mn> <mml:mo>×</mml:mo> </mml:math> increase in speed compared to iterative methods with a spatially varying model, and outperforms existing deep-learning-based methods that assume shift invariance.

Genomic deep learning models can predict genome-wide epigenetic features and gene expression levels directly from DNA sequence. While current models perform well at predicting gene expression levels across genes in different cell types from the reference genome, their ability to explain expression variation between individuals due to cis-regulatory genetic variants remains largely unexplored. Here, we evaluate four state-of-the-art models on paired personal genome and transcriptome data and find limited performance when explaining variation in expression across individuals. In addition, models often fail to predict the correct direction of effect of cis-regulatory genetic variation on expression.

Abstract Generative AI has the potential to redefine the process of therapeutic antibody discovery. In this report, we describe and validate deep generative models for the de novo design of antibodies against human epidermal growth factor receptor (HER2) without additional optimization. The models enabled an efficient workflow that combined in silico design methods with high-throughput experimental techniques to rapidly identify binders from a library of ∼10 6 heavy chain complementarity-determining region (HCDR) variants. We demonstrated that the workflow achieves binding rates of 10.6% for HCDR3 and 1.8% for HCDR123 designs and is statistically superior to baselines. We further characterized 421 diverse binders using surface plasmon resonance (SPR), finding 71 with low nanomolar affinity similar to the therapeutic anti-HER2 antibody trastuzumab. A selected subset of 11 diverse high-affinity binders were functionally equivalent or superior to trastuzumab, with most demonstrating suitable developability features. We designed one binder with ∼3x higher cell-based potency compared to trastuzumab and another with improved cross-species reactivity 1 . Our generative AI approach unlocks an accelerated path to designing therapeutic antibodies against diverse targets.

Proteins mediate their functions through chemical interactions; modeling these interactions, which are typically through sidechains, is an important need in protein design. However, constructing an all-atom generative model requires an appropriate scheme for managing the jointly continuous and discrete nature of proteins encoded in the structure and sequence. We describe an all-atom diffusion model of protein structure, Protpardelle, which represents all sidechain states at once as a "superposition" state; superpositions defining a protein are collapsed into individual residue types and conformations during sample generation. When combined with sequence design methods, our model is able to codesign all-atom protein structure and sequence. Generated proteins are of good quality under the typical quality, diversity, and novelty metrics, and sidechains reproduce the chemical features and behavior of natural proteins. Finally, we explore the potential of our model to conduct all-atom protein design and scaffold functional motifs in a backbone- and rotamer-free way.