ProGAE: A Geometric Autoencoder-based Generative Model for  Disentangling Protein Conformational Space
Authors: Norman Joseph Tatro, Payel Das, Pin-Yu Chen, Vijil Chenthamarakshan, Rongjie Lai
Keywords: generative models, deep learning, interpretability
Abstract: Understanding the protein conformational landscape is critical, as protein function, as well as modulations thereof due to ligand binding or changes in environment, are intimately connected with structural variations. This work focuses on learning a generative neural network on a simulated ensemble of protein structures obtained using molecular simulation to characterize the distinct structural fluctuations of a protein bound to various drug molecules. Specifically, we use a  geometric autoencoder framework to learn separate latent space encodings of  the intrinsic and extrinsic geometries of the system. For this purpose, the proposed Protein Geometric AutoEncoder (ProGAE) model is trained on  the length of the alpha-carbon pseudobonds and the  orientation of the backbone bonds of the protein. Using ProGAE latent embeddings, we reconstruct and generate the conformational ensemble of a protein at or near the experimental resolution. Empowered by the disentangled latent space learning, the intrinsic latent embedding help in geometric error correction, whereas the extrinsic latent embedding is successfully used for classification or property prediction of  different drugs bound to a specific protein. Additionally, ProGAE is able to be transferred to the structures of a different state of the same protein or to a completely different protein of different size, where only the dense layer decoding from the latent representation needs to be retrained. Results show that our geometric learning-based method enjoys both accuracy and efficiency for generating complex structural variations, charting the path toward scalable and improved approaches for analyzing and enhancing molecular simulations.