Grant M. Rotskoff

Frank Hu, Michael S. Chen, Grant M. Rotskoff et al. · stanford

Rapid determination of molecular structures can greatly accelerate workflows across many chemical disciplines. However, elucidating structure using only one-dimensional (1D) NMR spectra, the most readily accessible data, remains an extremely challenging problem because of the combinatorial explosion of the number of possible molecules as the number of constituent atoms is increased. Here, we introduce a multitask machine learning framework that predicts the molecular structure (formula and connectivity) of an unknown compound solely based on its 1D 1H and/or 13C NMR spectra. First, we show how a transformer architecture can be constructed to efficiently solve the task, traditionally performed by chemists, of assembling large numbers of molecular fragments into molecular structures. Integrating this capability with a convolutional neural network (CNN), we build an end-to-end model for predicting structure from spectra that is fast and accurate. We demonstrate the effectiveness of this framework on molecules with up to 19 heavy (non-hydrogen) atoms, a size for which there are trillions of possible structures. Without relying on any prior chemical knowledge such as the molecular formula, we show that our approach predicts the exact molecule 69.6% of the time within the first 15 predictions, reducing the search space by up to 11 orders of magnitude.

Luke Causer, Grant M. Rotskoff, Juan P. Garrahan · stanford

Diffusion models (DMs) are a class of generative machine learning methods that sample a target distribution by transforming samples of a trivial (often Gaussian) distribution using a learned stochastic differential equation. In standard DMs, this is done by learning a ``score function'' that reverses the effect of adding diffusive noise to the distribution of interest. Here we consider the generalisation of DMs to lattice systems with discrete degrees of freedom, and where noise is added via Markov chain jump dynamics. We show how to use tensor networks (TNs) to efficiently define and sample such ``discrete diffusion models'' (DDMs) without explicitly having to solve a stochastic differential equation. We show the following: (i) by parametrising the data and evolution operators as TNs, the denoising dynamics can be represented exactly; (ii) the auto-regressive nature of TNs allows to generate samples efficiently and without bias; (iii) for sampling Boltzmann-like distributions, TNs allow to construct an efficient learning scheme that integrates well with Monte Carlo. We illustrate this approach to study the equilibrium of two models with non-trivial thermodynamics, the $d=1$ constrained Fredkin chain and the $d=2$ Ising model.

Yinuo Ren, Haoxuan Chen, Yuchen Zhu et al. · gatech, stanford

Discrete diffusion models have emerged as a powerful generative modeling framework for discrete data with successful applications spanning from text generation to image synthesis. However, their deployment faces challenges due to the high dimensionality of the state space, necessitating the development of efficient inference algorithms. Current inference approaches mainly fall into two categories: exact simulation and approximate methods such as $τ$-leaping. While exact methods suffer from unpredictable inference time and redundant function evaluations, $τ$-leaping is limited by its first-order accuracy. In this work, we advance the latter category by tailoring the first extension of high-order numerical inference schemes to discrete diffusion models, enabling larger step sizes while reducing error. We rigorously analyze the proposed schemes and establish the second-order accuracy of the $θ$-trapezoidal method in KL divergence. Empirical evaluations on GPT-2 level text and ImageNet-level image generation tasks demonstrate that our method achieves superior sample quality compared to existing approaches under equivalent computational constraints.

Yinuo Ren, Grant M. Rotskoff, Lexing Ying · stanford

Probabilistic generative models based on measure transport, such as diffusion and flow-based models, are often formulated in the language of Markovian stochastic dynamics, where the choice of the underlying process impacts both algorithmic design choices and theoretical analysis. In this paper, we aim to establish a rigorous mathematical foundation for denoising Markov models, a broad class of generative models that postulate a forward process transitioning from the target distribution to a simple, easy-to-sample distribution, alongside a backward process particularly constructed to enable efficient sampling in the reverse direction. Leveraging deep connections with nonequilibrium statistical mechanics and generalized Doob's $h$-transform, we propose a minimal set of assumptions that ensure: (1) explicit construction of the backward generator, (2) a unified variational objective directly minimizing the measure transport discrepancy, and (3) adaptations of the classical score-matching approach across diverse dynamics. Our framework unifies existing formulations of continuous and discrete diffusion models, identifies the most general form of denoising Markov models under certain regularity assumptions on forward generators, and provides a systematic recipe for designing denoising Markov models driven by arbitrary Lévy-type processes. We illustrate the versatility and practical effectiveness of our approach through novel denoising Markov models employing geometric Brownian motion and jump processes as forward dynamics, highlighting the framework's potential flexibility and capability in modeling complex distributions.

Shriram Chennakesavalu, Frank Hu, Sebastian Ibarraran et al. · stanford

Searching through chemical space is an exceptionally challenging problem because the number of possible molecules grows combinatorially with the number of atoms. Large, autoregressive models trained on databases of chemical compounds have yielded powerful generators, but we still lack robust strategies for generating molecules with desired properties. This molecular search problem closely resembles the "alignment" problem for large language models, though for many chemical tasks we have a specific and easily evaluable reward function. Here, we introduce an algorithm called energy rank alignment (ERA) that leverages an explicit reward function to produce a gradient-based objective that we use to optimize autoregressive policies. We show theoretically that this algorithm is closely related to proximal policy optimization (PPO) and direct preference optimization (DPO), but has a minimizer that converges to an ideal Gibbs-Boltzmann distribution with the reward playing the role of an energy function. Furthermore, this algorithm is highly scalable, does not require reinforcement learning, and performs well relative to DPO when the number of preference observations per pairing is small. We deploy this approach to align molecular transformers and protein language models to generate molecules and protein sequences, respectively, with externally specified properties and find that it does so robustly, searching through diverse parts of chemical space.

Yinuo Ren, Wenhao Gao, Lexing Ying et al. · stanford

We study inference-time scaling for diffusion models, where the goal is to adapt a pre-trained model to new target distributions without retraining. Existing guidance-based methods are simple but introduce bias, while particle-based corrections suffer from weight degeneracy and high computational cost. We introduce DriftLite, a lightweight, training-free particle-based approach that steers the inference dynamics on the fly with provably optimal stability control. DriftLite exploits a previously unexplored degree of freedom in the Fokker-Planck equation between the drift and particle potential, and yields two practical instantiations: Variance- and Energy-Controlling Guidance (VCG/ECG) for approximating the optimal drift with minimal overhead. Across Gaussian mixture models, particle systems, and large-scale protein-ligand co-folding problems, DriftLite consistently reduces variance and improves sample quality over pure guidance and sequential Monte Carlo baselines. These results highlight a principled, efficient route toward scalable inference-time adaptation of diffusion models.

Yinuo Ren, Yiping Lu, Lexing Ying et al.

Inferring a diffusion equation from discretely-observed measurements is a statistical challenge of significant importance in a variety of fields, from single-molecule tracking in biophysical systems to modeling financial instruments. Assuming that the underlying dynamical process obeys a $d$-dimensional stochastic differential equation of the form $$\mathrm{d}\boldsymbol{x}_t=\boldsymbol{b}(\boldsymbol{x}_t)\mathrm{d} t+Σ(\boldsymbol{x}_t)\mathrm{d}\boldsymbol{w}_t,$$ we propose neural network-based estimators of both the drift $\boldsymbol{b}$ and the spatially-inhomogeneous diffusion tensor $D = ΣΣ^{T}$ and provide statistical convergence guarantees when $\boldsymbol{b}$ and $D$ are $s$-Hölder continuous. Notably, our bound aligns with the minimax optimal rate $N^{-\frac{2s}{2s+d}}$ for nonparametric function estimation even in the presence of correlation within observational data, which necessitates careful handling when establishing fast-rate generalization bounds. Our theoretical results are bolstered by numerical experiments demonstrating accurate inference of spatially-inhomogeneous diffusion tensors.

Shriram Chennakesavalu, Grant M. Rotskoff

Experimental advances enabling high-resolution external control create new opportunities to produce materials with exotic properties. In this work, we investigate how a multi-agent reinforcement learning approach can be used to design external control protocols for self-assembly. We find that a fully decentralized approach performs remarkably well even with a "coarse" level of external control. More importantly, we see that a partially decentralized approach, where we include information about the local environment allows us to better control our system towards some target distribution. We explain this by analyzing our approach as a partially-observed Markov decision process. With a partially decentralized approach, the agent is able to act more presciently, both by preventing the formation of undesirable structures and by better stabilizing target structures as compared to a fully decentralized approach.

Marylou Gabrié, Grant M. Rotskoff, Eric Vanden-Eijnden

Normalizing flows can generate complex target distributions and thus show promise in many applications in Bayesian statistics as an alternative or complement to MCMC for sampling posteriors. Since no data set from the target posterior distribution is available beforehand, the flow is typically trained using the reverse Kullback-Leibler (KL) divergence that only requires samples from a base distribution. This strategy may perform poorly when the posterior is complicated and hard to sample with an untrained normalizing flow. Here we explore a distinct training strategy, using the direct KL divergence as loss, in which samples from the posterior are generated by (i) assisting a local MCMC algorithm on the posterior with a normalizing flow to accelerate its mixing rate and (ii) using the data generated this way to train the flow. The method only requires a limited amount of \textit{a~priori} input about the posterior, and can be used to estimate the evidence required for model validation, as we illustrate on examples.

Zhengdao Chen, Grant M. Rotskoff, Joan Bruna et al.

Recent theoretical works have characterized the dynamics of wide shallow neural networks trained via gradient descent in an asymptotic mean-field limit when the width tends towards infinity. At initialization, the random sampling of the parameters leads to deviations from the mean-field limit dictated by the classical Central Limit Theorem (CLT). However, since gradient descent induces correlations among the parameters, it is of interest to analyze how these fluctuations evolve. Here, we use a dynamical CLT to prove that the asymptotic fluctuations around the mean limit remain bounded in mean square throughout training. The upper bound is given by a Monte-Carlo resampling error, with a variance that that depends on the 2-norm of the underlying measure, which also controls the generalization error. This motivates the use of this 2-norm as a regularization term during training. Furthermore, if the mean-field dynamics converges to a measure that interpolates the training data, we prove that the asymptotic deviation eventually vanishes in the CLT scaling. We also complement these results with numerical experiments.

Grant M. Rotskoff, Andrew R. Mitchell, Eric Vanden-Eijnden

Deep neural networks, when optimized with sufficient data, provide accurate representations of high-dimensional functions; in contrast, function approximation techniques that have predominated in scientific computing do not scale well with dimensionality. As a result, many high-dimensional sampling and approximation problems once thought intractable are being revisited through the lens of machine learning. While the promise of unparalleled accuracy may suggest a renaissance for applications that require parameterizing representations of complex systems, in many applications gathering sufficient data to develop such a representation remains a significant challenge. Here we introduce an approach that combines rare events sampling techniques with neural network optimization to optimize objective functions that are dominated by rare events. We show that importance sampling reduces the asymptotic variance of the solution to a learning problem, suggesting benefits for generalization. We study our algorithm in the context of learning dynamical transition pathways between two states of a system, a problem with applications in statistical physics and implications in machine learning theory. Our numerical experiments demonstrate that we can successfully learn even with the compounding difficulties of high-dimension and rare data.

Grant M. Rotskoff, Eric Vanden-Eijnden

Neural networks, a central tool in machine learning, have demonstrated remarkable, high fidelity performance on image recognition and classification tasks. These successes evince an ability to accurately represent high dimensional functions, but rigorous results about the approximation error of neural networks after training are few. Here we establish conditions for global convergence of the standard optimization algorithm used in machine learning applications, stochastic gradient descent (SGD), and quantify the scaling of its error with the size of the network. This is done by reinterpreting SGD as the evolution of a particle system with interactions governed by a potential related to the objective or "loss" function used to train the network. We show that, when the number $n$ of units is large, the empirical distribution of the particles descends on a convex landscape towards the global minimum at a rate independent of $n$, with a resulting approximation error that universally scales as $O(n^{-1})$. These properties are established in the form of a Law of Large Numbers and a Central Limit Theorem for the empirical distribution. Our analysis also quantifies the scale and nature of the noise introduced by SGD and provides guidelines for the step size and batch size to use when training a neural network. We illustrate our findings on examples in which we train neural networks to learn the energy function of the continuous 3-spin model on the sphere. The approximation error scales as our analysis predicts in as high a dimension as $d=25$.