The de Rham-Hodge Analysis and Modeling of Biomolecules.

Abstract

Biological macromolecules have intricate structures that underpin their biological functions. Understanding their structure-function relationships remains a challenge due to their structural complexity and functional variability. Although de Rham-Hodge theory, a landmark of twentieth-century mathematics, has had a tremendous impact on mathematics and physics, it has not been devised for macromolecular modeling and analysis. In this work, we introduce de Rham-Hodge theory as a unified paradigm for analyzing the geometry, topology, flexibility, and Hodge mode analysis of biological macromolecules. Geometric characteristics and topological invariants are obtained either from the Helmholtz-Hodge decomposition of the scalar, vector, and/or tensor fields of a macromolecule or from the spectral analysis of various Laplace-de Rham operators defined on the molecular manifolds. We propose Laplace-de Rham spectral-based models for predicting macromolecular flexibility. We further construct a Laplace-de Rham-Helfrich operator for revealing cryo-EM natural frequencies. Extensive experiments are carried out to demonstrate that the proposed de Rham-Hodge paradigm is one of the most versatile tools for the multiscale modeling and analysis of biological macromolecules and subcellular organelles. Accurate, reliable, and topological structure-preserving algorithms for implementing discrete exterior calculus (DEC) have been developed to facilitate the aforementioned modeling and analysis of biological macromolecules. The proposed de Rham-Hodge paradigm has potential applications to subcellular organelles and the structure construction from medium- or low-resolution cryo-EM maps, and functional predictions from massive biomolecular datasets.