Current directions in combining simulation-based macromolecular modeling approaches with deep learning

Introduction: Structure-guided drug discovery relies on accurate computational methods for modeling macromolecules. Simulations provide means of predicting macromolecular folds, of discovering function from structure, and of designing macromolecules to serve as drugs. Success rates are limited for any of these tasks, however. Recently, deep neural network-based methods have greatly enhanced the accuracy of predictions of protein structure from sequence, generating excitement about the potential impact of deep learning.Areas covered: This review introduces biologists to deep neural network architecture, surveys recent successes of deep learning in structure prediction, and discusses emerging deep learning-based approaches for structure-function analysis and design. Particular focus is given to the interplay between simulation-based and neural network-based approaches.Expert opinion: As deep learning grows integral to macromolecular modeling, simulation- and neural network-based approaches must grow more tightly interconnected. Modular software architecture must emerge allowing both types of tools to be combined with maximal versatility. Open sharing of code under permissive licenses will be essential. Although experiments will remain the gold standard for reliable information to guide drug discovery, we may soon see successful drug development projects based on high-accuracy predictions from algorithms that combine simulation with deep learning - the ultimate validation of this combination's power.