Machine learning-guided directed evolution for protein engineering

Machine learning (ML)-guided directed evolution is a new paradigm for biological design that enables optimization of complex functions. ML methods use data to predict how sequence maps to function without requiring a detailed model of the underlying physics or biological pathways. To demonstrate ML-guided directed evolution, we introduce the steps required to build ML sequence-function models and use them to guide engineering, making recommendations at each stage. This review covers basic concepts relevant to using ML for protein engineering as well as the current literature and applications of this new engineering paradigm. ML methods accelerate directed evolution by learning from information contained in all measured variants and using that information to select sequences that are likely to be improved. We then provide two case studies that demonstrate the ML-guided directed evolution process. We also look to future opportunities where ML will enable discovery of new protein functions and uncover the relationship between protein sequence and function.Comment: Made significant revisions to focus on aspects most relevant to applying machine learning to speed up directed evolutio

Preconditioned Stochastic Gradient Langevin Dynamics for Deep Neural Networks

Effective training of deep neural networks suffers from two main issues. The first is that the parameter spaces of these models exhibit pathological curvature. Recent methods address this problem by using adaptive preconditioning for Stochastic Gradient Descent (SGD). These methods improve convergence by adapting to the local geometry of parameter space. A second issue is overfitting, which is typically addressed by early stopping. However, recent work has demonstrated that Bayesian model averaging mitigates this problem. The posterior can be sampled by using Stochastic Gradient Langevin Dynamics (SGLD). However, the rapidly changing curvature renders default SGLD methods inefficient. Here, we propose combining adaptive preconditioners with SGLD. In support of this idea, we give theoretical properties on asymptotic convergence and predictive risk. We also provide empirical results for Logistic Regression, Feedforward Neural Nets, and Convolutional Neural Nets, demonstrating that our preconditioned SGLD method gives state-of-the-art performance on these models.Comment: AAAI 201

Confidence driven TGV fusion

We introduce a novel model for spatially varying variational data fusion, driven by point-wise confidence values. The proposed model allows for the joint estimation of the data and the confidence values based on the spatial coherence of the data. We discuss the main properties of the introduced model as well as suitable algorithms for estimating the solution of the corresponding biconvex minimization problem and their convergence. The performance of the proposed model is evaluated considering the problem of depth image fusion by using both synthetic and real data from publicly available datasets

Meta Reinforcement Learning with Latent Variable Gaussian Processes

Learning from small data sets is critical in many practical applications where data collection is time consuming or expensive, e.g., robotics, animal experiments or drug design. Meta learning is one way to increase the data efficiency of learning algorithms by generalizing learned concepts from a set of training tasks to unseen, but related, tasks. Often, this relationship between tasks is hard coded or relies in some other way on human expertise. In this paper, we frame meta learning as a hierarchical latent variable model and infer the relationship between tasks automatically from data. We apply our framework in a model-based reinforcement learning setting and show that our meta-learning model effectively generalizes to novel tasks by identifying how new tasks relate to prior ones from minimal data. This results in up to a 60% reduction in the average interaction time needed to solve tasks compared to strong baselines.Comment: 11 pages, 7 figure

Bayesian field theoretic reconstruction of bond potential and bond mobility in single molecule force spectroscopy

Quantifying the forces between and within macromolecules is a necessary first step in understanding the mechanics of molecular structure, protein folding, and enzyme function and performance. In such macromolecular settings, dynamic single-molecule force spectroscopy (DFS) has been used to distort bonds. The resulting responses, in the form of rupture forces, work applied, and trajectories of displacements, have been used to reconstruct bond potentials. Such approaches often rely on simple parameterizations of one-dimensional bond potentials, assumptions on equilibrium starting states, and/or large amounts of trajectory data. Parametric approaches typically fail at inferring complex-shaped bond potentials with multiple minima, while piecewise estimation may not guarantee smooth results with the appropriate behavior at large distances. Existing techniques, particularly those based on work theorems, also do not address spatial variations in the diffusivity that may arise from spatially inhomogeneous coupling to other degrees of freedom in the macromolecule, thereby presenting an incomplete picture of the overall bond dynamics. To solve these challenges, we have developed a comprehensive empirical Bayesian approach that incorporates data and regularization terms directly into a path integral. All experiemental and statistical parameters in our method are estimated empirically directly from the data. Upon testing our method on simulated data, our regularized approach requires fewer data and allows simultaneous inference of both complex bond potentials and diffusivity profiles.Comment: In review - Python source code available on github. Abridged abstract on arXi

A spin glass model for reconstructing nonlinearly encrypted signals corrupted by noise

An encryption of a signal ${\bf s}\in\mathbb{R^N}$ is a random mapping ${\bf s}\mapsto \textbf{y}=(y_1,\ldots,y_M)^T\in \mathbb{R}^M$ which can be corrupted by an additive noise. Given the Encryption Redundancy Parameter (ERP) $\mu=M/N\ge 1$, the signal strength parameter $R=\sqrt{\sum_i s_i^2/N}$, and the ('bare') noise-to-signal ratio (NSR) $\gamma\ge 0$, we consider the problem of reconstructing ${\bf s}$ from its corrupted image by a Least Square Scheme for a certain class of random Gaussian mappings. The problem is equivalent to finding the configuration of minimal energy in a certain version of spherical spin glass model, with squared Gaussian-distributed random potential. We use the Parisi replica symmetry breaking scheme to evaluate the mean overlap $p_{\infty}\in [0,1]$ between the original signal and its recovered image (known as 'estimator') as $N\to \infty$, which is a measure of the quality of the signal reconstruction. We explicitly analyze the general case of linear-quadratic family of random mappings and discuss the full $p_{\infty} (\gamma)$ curve. When nonlinearity exceeds a certain threshold but redundancy is not yet too big, the replica symmetric solution is necessarily broken in some interval of NSR. We show that encryptions with a nonvanishing linear component permit reconstructions with $p_{\infty}>0$ for any $\mu>1$ and any $\gamma<\infty$, with $p_{\infty}\sim \gamma^{-1/2}$ as $\gamma\to \infty$. In contrast, for the case of purely quadratic nonlinearity, for any ERP $\mu>1$ there exists a threshold NSR value $\gamma_c(\mu)$ such that $p_{\infty}=0$ for $\gamma>\gamma_c(\mu)$ making the reconstruction impossible. The behaviour close to the threshold is given by $p_{\infty}\sim (\gamma_c-\gamma)^{3/4}$ and is controlled by the replica symmetry breaking mechanism.Comment: 33 pages, 5 figure