Massive molecular simulations of drug-target proteins have been used as a tool to understand disease mechanism and develop therapeutics. This work focuses on learning a generative neural network on a structural ensemble of a drug-target protein, e.g. SARS-CoV-2 Spike protein, obtained from computationally expensive molecular simulations. Model tasks involve characterizing the distinct structural fluctuations of the protein bound to various drug molecules, as well as efficient generation of protein conformations that can serve as an complement of a molecular simulation engine. Specifically, we present a geometric autoencoder framework to learn separate latent space encodings of the intrinsic and extrinsic geometries of the protein structure. For this purpose, the proposed Protein Geometric AutoEncoder (ProGAE) model is trained on the protein contact map and the orientation of the backbone bonds of the protein. Using ProGAE latent embeddings, we reconstruct and generate the conformational ensemble of a protein at or near the experimental resolution, while gaining better interpretability and controllability in term of protein structure generation from the learned latent space. Additionally, ProGAE models are transferable to a different state of the same protein or to a new protein of different size, where only the dense layer decoding from the latent representation needs to be retrained. Results show that our geometric learning-based method enjoys both accuracy and efficiency for generating complex structural variations, charting the path toward scalable and improved approaches for analyzing and enhancing high-cost simulations of drug-target proteins.

We propose a novel algorithm, Salient Conditional Diffusion (Sancdifi), a state-of-the-art defense against backdoor attacks. Sancdifi uses a denoising diffusion probabilistic model (DDPM) to degrade an image with noise and then recover said image using the learned reverse diffusion. Critically, we compute saliency map-based masks to condition our diffusion, allowing for stronger diffusion on the most salient pixels by the DDPM. As a result, Sancdifi is highly effective at diffusing out triggers in data poisoned by backdoor attacks. At the same time, it reliably recovers salient features when applied to clean data. This performance is achieved without requiring access to the model parameters of the Trojan network, meaning Sancdifi operates as a black-box defense.