Plug & Play Directed Evolution of Proteins with Gradient-based Discrete MCMC

A long-standing goal of machine-learning-based protein engineering is to accelerate the discovery of novel mutations that improve the function of a known protein. We introduce a sampling framework for evolving proteins in silico that supports mixing and matching a variety of unsupervised models, such as protein language models, and supervised models that predict protein function from sequence. By composing these models, we aim to improve our ability to evaluate unseen mutations and constrain search to regions of sequence space likely to contain functional proteins. Our framework achieves this without any model fine-tuning or re-training by constructing a product of experts distribution directly in discrete protein space. Instead of resorting to brute force search or random sampling, which is typical of classic directed evolution, we introduce a fast MCMC sampler that uses gradients to propose promising mutations. We conduct in silico directed evolution experiments on wide fitness landscapes and across a range of different pre-trained unsupervised models, including a 650M parameter protein language model. Our results demonstrate an ability to efficiently discover variants with high evolutionary likelihood as well as estimated activity multiple mutations away from a wild type protein, suggesting our sampler provides a practical and effective new paradigm for machine-learning-based protein engineering.

Smoothed Analysis in Unsupervised Learning via Decoupling

Smoothed analysis is a powerful paradigm in overcoming worst-case intractability in unsupervised learning and high-dimensional data analysis. While polynomial time smoothed analysis guarantees have been obtained for worst-case intractable problems like tensor decompositions and learning mixtures of Gaussians, such guarantees have been hard to obtain for several other important problems in unsupervised learning. A core technical challenge is obtaining lower bounds on the least singular value for random matrix ensembles with dependent entries, that are given by low-degree polynomials of a few base underlying random variables. In this work, we address this challenge by obtaining high-confidence lower bounds on the least singular value of new classes of structured random matrix ensembles of the above kind. We then use these bounds to obtain polynomial time smoothed analysis guarantees for the following three important problems in unsupervised learning: 1. Robust subspace recovery, when the fraction $\alpha$ of inliers in the d-dimensional subspace $T \subset \mathbb{R}^n$ is at least $\alpha > (d/n)^\ell$ for any constant integer $\ell>0$. This contrasts with the known worst-case intractability when $\alpha< d/n$, and the previous smoothed analysis result which needed $\alpha > d/n$ (Hardt and Moitra, 2013). 2. Higher order tensor decompositions, where we generalize the so-called FOOBI algorithm of Cardoso to find order-$\ell$ rank-one tensors in a subspace. This allows us to obtain polynomially robust decomposition algorithms for $2\ell$'th order tensors with rank $O(n^{\ell})$. 3. Learning overcomplete hidden markov models, where the size of the state space is any polynomial in the dimension of the observations. This gives the first polynomial time guarantees for learning overcomplete HMMs in a smoothed analysis model.