Substituted Oligosaccharides as Protein Mimics: Deep Learning Free Energy Landscapes

Protein-protein complexes power the majority of cellular processes. Interfering with the formation of such complexes using well-designed mimics is a difficult, yet actively pursued, research endeavor. Due to the limited availability of results on the conformational preferences of oligosaccharides compared to polypeptides, the former have been much less explored than the latter as protein mimics, despite interesting ADMET characteristics. In this work, the conformational landscapes of a series of 956 substituted glucopyranose oligomers of lengths 3 to 12 designed as protein interface mimics are revealed using microsecond-time-scale, enhanced-sampling molecular dynamics simulations. Deep convolutional networks are trained on these large conformational ensembles, to predict the stability of longer oligosaccharide structures from those of their constituent trimer motifs. Deep generative adversarial networks are then designed to suggest plausible conformations for oligosaccharide mimics of arbitrary length and substituent sequences that can subsequently be used as input to docking simulations. Analyzing the performance of the neural networks also yields insights into the intricate collective effects that dominate oligosaccharide conformational dynamics.