On Diffusion Posterior Sampling via Sequential Monte Carlo for Zero-Shot Scaffolding of Protein Motifs

With the advent of diffusion models, new proteins can be generated at an unprecedented rate. The \textit{motif scaffolding problem} requires steering this generative process to yield proteins with a desirable functional substructure -- a motif. While models have been trained to take the motif as conditional input, recent techniques in diffusion posterior sampling can be leveraged as zero-shot alternatives whose approximations can be corrected with sequential Monte Carlo (SMC) algorithms. In this work, we introduce a new set of guidance potentials to describe and solve scaffolding tasks by adapting SMC-aided diffusion posterior samplers with an unconditional model, Genie, acting as a prior. Against established benchmarks, we successfully scaffold several single-motif and multi-motif problems. The latter is possible by pairing reconstruction guidance with $\mathrm{SE}(3)$-invariant potentials. In the single-motif case, we find these potentials perform comparably to the conventional masking approach and that reconstruction guidance outperforms replacement methods when aided with SMC. We additionally consider a guidance potential for point symmetry constraints and produce designable internally symmetric monomers with our setup. Overall, this work highlights the capabilities and areas for improvement of zero-shot posterior samplers in motif scaffolding tasks. Code is available at: https://github.com/matsagad/mres-project

A Primer on Variational Inference for Physics-Informed Deep Generative Modelling

Variational inference (VI) is a computationally efficient and scalable methodology for approximate Bayesian inference. It strikes a balance between accuracy of uncertainty quantification and practical tractability. It excels at generative modelling and inversion tasks due to its built-in Bayesian regularisation and flexibility, essential qualities for physics related problems. Deriving the central learning objective for VI must often be tailored to new learning tasks where the nature of the problems dictates the conditional dependence between variables of interest, such as arising in physics problems. In this paper, we provide an accessible and thorough technical introduction to VI for forward and inverse problems, guiding the reader through standard derivations of the VI framework and how it can best be realized through deep learning. We then review and unify recent literature exemplifying the creative flexibility allowed by VI. This paper is designed for a general scientific audience looking to solve physics-based problems with an emphasis on uncertainty quantification.

Kinetic Interacting Particle Langevin Monte Carlo

This paper introduces and analyses interacting underdamped Langevin algorithms, termed Kinetic Interacting Particle Langevin Monte Carlo (KIPLMC) methods, for statistical inference in latent variable models. We propose a diffusion process that evolves jointly in the space of parameters and latent variables and exploit the fact that the stationary distribution of this diffusion concentrates around the maximum marginal likelihood estimate of the parameters. We then provide two explicit discretisations of this diffusion as practical algorithms to estimate parameters of statistical models. For each algorithm, we obtain nonasymptotic rates of convergence for the case where the joint log-likelihood is strongly concave with respect to latent variables and parameters. In particular, we provide convergence analysis for the diffusion together with the discretisation error, providing convergence rate estimates for the algorithms in Wasserstein-2 distance. To demonstrate the utility of the introduced methodology, we provide numerical experiments that demonstrate the effectiveness of the proposed diffusion for statistical inference and the stability of the numerical integrators utilised for discretisation. Our setting covers a broad number of applications, including unsupervised learning, statistical inference, and inverse problems.

Proximal Interacting Particle Langevin Algorithms

We introduce a class of algorithms, termed Proximal Interacting Particle Langevin Algorithms (PIPLA), for inference and learning in latent variable models whose joint probability density is non-differentiable. Leveraging proximal Markov chain Monte Carlo (MCMC) techniques and the recently introduced interacting particle Langevin algorithm (IPLA), we propose several variants within the novel proximal IPLA family, tailored to the problem of estimating parameters in a non-differentiable statistical model. We prove nonasymptotic bounds for the parameter estimates produced by multiple algorithms in the strongly log-concave setting and provide comprehensive numerical experiments on various models to demonstrate the effectiveness of the proposed methods. In particular, we demonstrate the utility of the proposed family of algorithms on a toy hierarchical example where our assumptions can be checked, as well as on the problems of sparse Bayesian logistic regression, sparse Bayesian neural network, and sparse matrix completion. Our theory and experiments together show that PIPLA family can be the de facto choice for parameter estimation problems in latent variable models for non-differentiable models.

Efficient Prior Calibration From Indirect Data

Bayesian inversion is central to the quantification of uncertainty within problems arising from numerous applications in science and engineering. To formulate the approach, four ingredients are required: a forward model mapping the unknown parameter to an element of a solution space, often the solution space for a differential equation; an observation operator mapping an element of the solution space to the data space; a noise model describing how noise pollutes the observations; and a prior model describing knowledge about the unknown parameter before the data is acquired. This paper is concerned with learning the prior model from data; in particular, learning the prior from multiple realizations of indirect data obtained through the noisy observation process. The prior is represented, using a generative model, as the pushforward of a Gaussian in a latent space; the pushforward map is learned by minimizing an appropriate loss function. A metric that is well-defined under empirical approximation is used to define the loss function for the pushforward map to make an implementable methodology. Furthermore, an efficient residual-based neural operator approximation of the forward model is proposed and it is shown that this may be learned concurrently with the pushforward map, using a bilevel optimization formulation of the problem; this use of neural operator approximation has the potential to make prior learning from indirect data more computationally efficient, especially when the observation process is expensive, non-smooth or not known. The ideas are illustrated with the Darcy flow inverse problem of finding permeability from piezometric head measurements.