SentRNA: Improving computational RNA design by incorporating a prior of human design strategies

SentRNA: Improving computational RNA design by incorporating a prior of human design strategies Jade Shi, EteRNA players, Rhiju Das, and Vijay S. Pande Abstract: Designing RNA sequences that fold into specific structures and perform desired biological functions is an emerging field in bioengineering with broad applications from intracellular chemical catalysis to cancer therapy via selective gene silencing. Effective RNA design requires first solving the inverse folding problem: given a target structure, propose a sequence that folds into that structure. Although significant progress has been made in developing computational algorithms for this purpose, current approaches are ineffective at designing sequences for complex targets, limiting their utility in real-world applications. However, an alternative that has shown significantly higher performance are human players of the online RNA design game EteRNA. Through many rounds of gameplay, these players have developed a collective library of "human" rules and strategies for RNA design that have proven to be more effective than current computational approaches, especially for complex targets. Here, we present an RNA design agent, SentRNA, which consists of a fully-connected neural network trained using the eternasolves dataset, a set of 1.8 x 10 The agent first predicts an initial sequence for a target using the trained network, and then refines that solution if necessary using a short adaptive walk utilizing a canon of standard design moves. Through this approach, we observe SentRNA can learn and apply humanlike design strategies to solve several complex targets previously unsolvable by any computational approach. We thus demonstrate that incorporating a prior of human design strategies into a computational agent can significantly boost its performance, and suggests a new paradigm for machine-based RNA design. Introduction: Solving the inverse folding problem for RNA is a critical prerequisite to effective RNA design, an emerging field of modern bioengineering research. A RNA molecule's function is highly dependent on the structure into which it folds, which in turn is determined by the sequence of nucleotides that comprise it. Therefore, designing RNA molecules to perform specific functions requires designing sequences that fold into specific structures. As such, significant efforts have been made over the past several decades in developing computational algorithms to reliably predict RNA sequences that fold into a given target. Existing computational methods for inverse RNA folding can be roughly separated into two types. The first type generates an initial guess of a sequence and then refines the sequence using some form of stochastic search.