3D molecule generation by denoising voxel grids

We propose a new score-based approach to generate 3D molecules represented as atomic densities on regular grids. First, we train a denoising neural network that learns to map from a smooth distribution of noisy molecules to the distribution of real molecules. Then, we follow the neural empirical Bayes framework [Saremi and Hyvarinen, 2019] and generate molecules in two steps: (i) sample noisy density grids from a smooth distribution via underdamped Langevin Markov chain Monte Carlo, and (ii) recover the ``clean'' molecule by denoising the noisy grid with a single step. Our method, VoxMol, generates molecules in a fundamentally different way than the current state of the art (i.e., diffusion models applied to atom point clouds). It differs in terms of the data representation, the noise model, the network architecture and the generative modeling algorithm. VoxMol achieves comparable results to state of the art on unconditional 3D molecule generation while being simpler to train and faster to generate molecules.

Protein Discovery with Discrete Walk-Jump Sampling

We resolve difficulties in training and sampling from a discrete generative model by learning a smoothed energy function, sampling from the smoothed data manifold with Langevin Markov chain Monte Carlo (MCMC), and projecting back to the true data manifold with one-step denoising. Our Discrete Walk-Jump Sampling formalism combines the maximum likelihood training of an energy-based model and improved sample quality of a score-based model, while simplifying training and sampling by requiring only a single noise level. We evaluate the robustness of our approach on generative modeling of antibody proteins and introduce the distributional conformity score to benchmark protein generative models. By optimizing and sampling from our models for the proposed distributional conformity score, 97-100% of generated samples are successfully expressed and purified and 35% of functional designs show equal or improved binding affinity compared to known functional antibodies on the first attempt in a single round of laboratory experiments. We also report the first demonstration of long-run fast-mixing MCMC chains where diverse antibody protein classes are visited in a single MCMC chain.

Chain of Log-Concave Markov Chains

Markov chain Monte Carlo (MCMC) is a class of general-purpose algorithms for sampling from unnormalized densities. There are two well-known problems facing MCMC in high dimensions: (i) The distributions of interest are concentrated in pockets separated by large regions with small probability mass, and (ii) The log-concave pockets themselves are typically ill-conditioned. We introduce a framework to tackle these problems using isotropic Gaussian smoothing. We prove one can always decompose sampling from a density (minimal assumptions made on the density) into a sequence of sampling from log-concave conditional densities via accumulation of noisy measurements with equal noise levels. This construction keeps track of a history of samples, making it non-Markovian as a whole, but the history only shows up in the form of an empirical mean, making the memory footprint minimal. Our sampling algorithm generalizes walk-jump sampling [1]. The "walk" phase becomes a (non-Markovian) chain of log-concave Langevin chains. The "jump" from the accumulated measurements is obtained by empirical Bayes. We study our sampling algorithm quantitatively using the 2-Wasserstein metric and compare it with various Langevin MCMC algorithms. We also report a remarkable capacity of our algorithm to "tunnel" between modes of a distribution.

Universal Smoothed Score Functions for Generative Modeling

We consider the problem of generative modeling based on smoothing an unknown density of interest in $\mathbb{R}^d$ using factorial kernels with $M$ independent Gaussian channels with equal noise levels introduced by Saremi and Srivastava (2022). First, we fully characterize the time complexity of learning the resulting smoothed density in $\mathbb{R}^{Md}$, called M-density, by deriving a universal form for its parametrization in which the score function is by construction permutation equivariant. Next, we study the time complexity of sampling an M-density by analyzing its condition number for Gaussian distributions. This spectral analysis gives a geometric insight on the "shape" of M-densities as one increases $M$. Finally, we present results on the sample quality in this class of generative models on the CIFAR-10 dataset where we report Fr\'echet inception distances (14.15), notably obtained with a single noise level on long-run fast-mixing MCMC chains.

PropertyDAG: Multi-objective Bayesian optimization of partially ordered, mixed-variable properties for biological sequence design

Bayesian optimization offers a sample-efficient framework for navigating the exploration-exploitation trade-off in the vast design space of biological sequences. Whereas it is possible to optimize the various properties of interest jointly using a multi-objective acquisition function, such as the expected hypervolume improvement (EHVI), this approach does not account for objectives with a hierarchical dependency structure. We consider a common use case where some regions of the Pareto frontier are prioritized over others according to a specified $\textit{partial ordering}$ in the objectives. For instance, when designing antibodies, we would like to maximize the binding affinity to a target antigen only if it can be expressed in live cell culture -- modeling the experimental dependency in which affinity can only be measured for antibodies that can be expressed and thus produced in viable quantities. In general, we may want to confer a partial ordering to the properties such that each property is optimized conditioned on its parent properties satisfying some feasibility condition. To this end, we present PropertyDAG, a framework that operates on top of the traditional multi-objective BO to impose this desired ordering on the objectives, e.g. expression $\rightarrow$ affinity. We demonstrate its performance over multiple simulated active learning iterations on a penicillin production task, toy numerical problem, and a real-world antibody design task.

Multimeasurement Generative Models

We formally map the problem of sampling from an unknown distribution with density $p_X$ in $\mathbb{R}^d$ to the problem of learning and sampling $p_\mathbf{Y}$ in $\mathbb{R}^{Md}$ obtained by convolving $p_X$ with a fixed factorial kernel: $p_\mathbf{Y}$ is referred to as M-density and the factorial kernel as multimeasurement noise model (MNM). The M-density is smoother than $p_X$, easier to learn and sample from, yet for large $M$ the two problems are mathematically equivalent since $X$ can be estimated exactly given $\mathbf{Y}=\mathbf{y}$ using the Bayes estimator $\widehat{x}(\mathbf{y})=\mathbb{E}[X\vert\mathbf{Y}=\mathbf{y}]$. To formulate the problem, we derive $\widehat{x}(\mathbf{y})$ for Poisson and Gaussian MNMs expressed in closed form in terms of unnormalized $p_\mathbf{Y}$. This leads to a simple least-squares objective for learning parametric energy and score functions. We present various parametrization schemes of interest, including one in which studying Gaussian M-densities directly leads to multidenoising autoencoders--this is the first theoretical connection made between denoising autoencoders and empirical Bayes in the literature. Samples from $p_X$ are obtained by walk-jump sampling (Saremi & Hyvarinen, 2019) via underdamped Langevin MCMC (walk) to sample from $p_\mathbf{Y}$ and the multimeasurement Bayes estimation of $X$ (jump). We study permutation invariant Gaussian M-densities on MNIST, CIFAR-10, and FFHQ-256 datasets, and demonstrate the effectiveness of this framework for realizing fast-mixing stable Markov chains in high dimensions.

Automatic design of novel potential 3CL$^{\text{pro}}$ and PL$^{\text{pro}}$ inhibitors

With the goal of designing novel inhibitors for SARS-CoV-1 and SARS-CoV-2, we propose the general molecule optimization framework, Molecular Neural Assay Search (MONAS), consisting of three components: a property predictor which identifies molecules with specific desirable properties, an energy model which approximates the statistical similarity of a given molecule to known training molecules, and a molecule search method. In this work, these components are instantiated with graph neural networks (GNNs), Deep Energy Estimator Networks (DEEN) and Monte Carlo tree search (MCTS), respectively. This implementation is used to identify 120K molecules (out of 40-million explored) which the GNN determined to be likely SARS-CoV-1 inhibitors, and, at the same time, are statistically close to the dataset used to train the GNN.

Unnormalized Variational Bayes

We unify empirical Bayes and variational Bayes for approximating unnormalized densities. This framework, named unnormalized variational Bayes (UVB), is based on formulating a latent variable model for the random variable $Y=X+N(0,\sigma^2 I_d)$ and using the evidence lower bound (ELBO), computed by a variational autoencoder, as a parametrization of the energy function of $Y$ which is then used to estimate $X$ with the empirical Bayes least-squares estimator. In this intriguing setup, the $\textit{gradient}$ of the ELBO with respect to noisy inputs plays the central role in learning the energy function. Empirically, we demonstrate that UVB has a higher capacity to approximate energy functions than the parametrization with MLPs as done in neural empirical Bayes (DEEN). We especially showcase $\sigma=1$, where the differences between UVB and DEEN become visible and qualitative in the denoising experiments. For this high level of noise, the distribution of $Y$ is very smoothed and we demonstrate that one can traverse in a single run $-$ without a restart $-$ all MNIST classes in a variety of styles via walk-jump sampling with a fast-mixing Langevin MCMC sampler. We finish by probing the encoder/decoder of the trained models and confirm UVB $\neq$ VAE.

Learning and Inference in Imaginary Noise Models

Inspired by recent developments in learning smoothed densities with empirical Bayes, we study variational autoencoders with a decoder that is tailored for the random variable $Y=X+N(0,\sigma^2 I_d)$. A notion of smoothed variational inference emerges where the smoothing is implicitly enforced by the noise model of the decoder; "implicit", since during training the encoder only sees clean samples. This is the concept of imaginary noise model, where the noise model dictates the functional form of the variational lower bound $\mathcal{L}(\sigma)$, but the noisy data are never seen during learning. The model is named $\sigma$-VAE. We prove that all $\sigma$-VAEs are equivalent to each other via a simple $\beta$-VAE expansion: $\mathcal{L}(\sigma_2) \equiv \mathcal{L}(\sigma_1,\beta)$, where $\beta=\sigma_2^2/\sigma_1^2$. We prove a similar result for the Laplace distribution in exponential families. Empirically, we report an intriguing power law $\mathcal{D}_{\rm KL} \sim \sigma^{-\nu}$ for the learned models and we study the inference in the $\sigma$-VAE for unseen noisy data. The experiments were performed on MNIST, where we show that quite remarkably the model can make reasonable inferences on extremely noisy samples even though it has not seen any during training. The vanilla VAE completely breaks down in this regime. We finish with a hypothesis (the XYZ hypothesis) on the findings here.