Internal-Coordinate Density Modelling of Protein Structure: Covariance Matters

Published: 28 May 2024, Last Modified: 28 May 2024Accepted by TMLREveryoneRevisionsBibTeX
Abstract: After the recent ground-breaking advances in protein structure prediction, one of the remaining challenges in protein machine learning is to reliably predict distributions of structural states. Parametric models of fluctuations are difficult to fit due to complex covariance structures between degrees of freedom in the protein chain, often causing models to either violate local or global structural constraints. In this paper, we present a new strategy for modelling protein densities in internal coordinates, which uses constraints in 3D space to induce covariance structure between the internal degrees of freedom. We illustrate the potential of the procedure by constructing a variational autoencoder with full covariance output induced by the constraints implied by the conditional mean in 3D, and demonstrate that our approach makes it possible to scale density models of internal coordinates to full protein backbones in two settings: 1) a unimodal setting for proteins exhibiting small fluctuations and limited amounts of available data, and 2) a multimodal setting for larger conformational changes in a high data regime.
Submission Length: Regular submission (no more than 12 pages of main content)
Assigned Action Editor: ~Patrick_Flaherty1
Submission Number: 2092