Predicting the Functional Impact of KCNQ1 Variants with Artificial Neural Networks

Recent advances in experimental and computational protein structure determination have provided access to high-quality structures for most human proteins and mutants thereof. However, linking changes in structure in protein mutants to functional impact remains an active area of method development. If successful, such methods can ultimately assist physicians in taking appropriate treatment decisions. This work presents three artificial neural network (ANN)-based predictive models that classify four key functional parameters of KCNQ1 variants as normal or dysfunctional using PSSM-based evolutionary and/or biophysical descriptors. Recent advances in predicting protein structure and variant properties with artificial intelligence (AI) rely heavily on the availability of evolutionary features and thus fail to directly assess the biophysical underpinnings of a change in structure and/or function. The central goal of this work was to develop an ANN model based on structure and physiochemical properties of KCNQ1 potassium channels that performs comparably or better than algorithms using only on PSSM-based evolutionary features. These biophysical features highlight the structure-function relationships that govern protein stability, function, and regulation. The input sensitivity algorithm incorporates the roles of hydrophobicity, polarizability, and functional densities on key functional parameters of the KCNQ1 channel. Inclusion of the biophysical features outperforms exclusive use of PSSM-based evolutionary features in predicting activation voltage dependence and deactivation time. As AI is increasing applied to problems in biology, biophysical understanding will be critical with respect to ‘explainable AI’, i.e., understanding the relation of sequence, structure, and function of proteins. Our model is available at [www.kcnq1predict.org][1]. Author summary Heartbeat is maintained by electrical impulses generated by ion-conducting channel proteins in the heart such as the KCNQ1 potassium channel. Pathogenic variants in KCNQ1 can lead to channel loss-of-function and predisposition to fatal life-threatening irregularities of heart rhythm (arrhythmia). Machine learning methods that can predict the outcome of a mutation on KCNQ1 structure and function would be of great value in helping to assess the risk of a heart rhythm disorder. Recently, machine learning has made great progress in predicting the structures of proteins from their sequences. However, there are limited studies that link the effect of a mutation and change in protein structure with its function. This work presents the development of neural network models designed to predict mutation-induced changes in KCNQ1 functional parameters such as peak current density and voltage dependence of activation. We compare the predictive ability of features extracted from sequence, structure, and physicochemical properties of KCNQ1. Moreover, input sensitivity analysis connects biophysical features with specific functional parameters that provides insight into underlying molecular mechanisms for KCNQ1 channels. The best performing neural network model is publicly available as a webserver, called Q1VarPredBio, that delivers predictions about the functional phenotype of KCNQ1 variants. ### Competing Interest Statement The authors have declared no competing interest. [1]: http://www.kcnq1predict.org