Thomas Hamelryck

Thomas Hamelryck, Kanti V. Mardia

The seminal breakthrough of AlphaFold in protein structure prediction relied on a learned potential energy function parameterized by deep models, in contrast to its successors AlphaFold2 and AlphaFold3, which lack an explicit probabilistic interpretation. While AlphaFold's potential was originally justified by heuristic analogy to physical potentials of mean force, we show that it can instead be understood as a principled instance of probability kinematics (PK), also known as Jeffrey conditioning, a generalization of Bayesian updating. This reinterpretation reveals that AlphaFold is a generalized Bayesian model that explicitly defines a posterior distribution over structures, providing a deeper explanation of its success and a foundation for future model design. To demonstrate this framework with precision, we introduce a tractable synthetic model in which an angular random walk prior is updated with distance-based evidence via PK, directly mirroring AlphaFold's mechanism. This setting allows us to explore the probabilistic foundations of AlphaFold in a clear and interpretable way. Our work connects a landmark in protein structure prediction to a broader class of compositional deep generative models and points to new opportunities for principled probabilistic approaches.

Joseph Margaryan, Thomas Hamelryck

Critical applications in areas such as medicine, robotics and autonomous systems require compact (i.e., memory efficient), uncertainty-aware neural networks suitable for edge and other resource-constrained deployments. We study compact spectral circulant and block-circulant-with-circulant-blocks (BCCB) layers: FFT-diagonalizable circular convolutions whose weights live directly in the real FFT (RFFT) half (1D) or half-plane (2D). Parameterizing filters in the frequency domain lets us impose simple spectral structure, perform structured variational inference in a low-dimensional weight space, and calculate exact layer spectral norms, enabling inexpensive global Lipschitz bounds and margin-based robustness diagnostics. By placing independent complex Gaussians on the Hermitian support we obtain a discrete instance of the spectral representation of stationary kernels, inducing an exact stationary Gaussian-process prior over filters on the discrete circle/torus. We exploit this to define a practical spectral prior and a Hermitian-aware low-rank-plus-diagonal variational posterior in real coordinates. Empirically, spectral circulant/BCCB layers are effective compact building blocks in both (variational) Bayesian and point estimate regimes: compact Bayesian neural networks on MNIST->Fashion-MNIST, variational heads on frozen CIFAR-10 features, and deterministic ViT projections on CIFAR-10/Tiny ImageNet; spectral layers match strong baselines while using substantially fewer parameters and with tighter Lipschitz certificates.

Ola Rønning, Eric Nalisnick, Christophe Ley et al.

Stein variational gradient descent (SVGD) [Liu and Wang, 2016] performs approximate Bayesian inference by representing the posterior with a set of particles. However, SVGD suffers from variance collapse, i.e. poor predictions due to underestimating uncertainty [Ba et al., 2021], even for moderately-dimensional models such as small Bayesian neural networks (BNNs). To address this issue, we generalize SVGD by letting each particle parameterize a component distribution in a mixture model. Our method, Stein Mixture Inference (SMI), optimizes a lower bound to the evidence (ELBO) and introduces user-specified guides parameterized by particles. SMI extends the Nonlinear SVGD framework [Wang and Liu, 2019] to the case of variational Bayes. SMI effectively avoids variance collapse, judging by a previously described test developed for this purpose, and performs well on standard data sets. In addition, SMI requires considerably fewer particles than SVGD to accurately estimate uncertainty for small BNNs. The synergistic combination of NSVGD, ELBO optimization and user-specified guides establishes a promising approach towards variational Bayesian inference in the case of tall and wide data.