Construction of a Deep Neural Network Energy Function for Protein Physics

• Published in: Journal of chemical theory and computation Vol. 18; no. 9; pp. 5649 - 5658
• Main Authors: Yang, Huan, Xiong, Zhaoping, Zonta, Francesco
• Format: Journal Article
• Language: English
• Published: Washington American Chemical Society 13.09.2022
• Subjects: Amino acids; Artificial neural networks; Biology; Biomolecular Systems; Biomolecules; Data acquisition; Decoys; Energy; Machine learning; Neural networks; Parameterization; Proteins; Structural models
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.2c00069

The traditional approach of computational biology consists of calculating molecule properties by using approximate classical potentials. Interactions between atoms are described by an energy function derived from physical principles or fitted to experimental data. Their functional form is usually limited to pairwise interactions between atoms and does not consider complex multibody effects. More recently, neural networks have emerged as an alternative way of describing the interactions between biomolecules. In this approach, the energy function does not have an explicit functional form and is learned bottom-up from simulations at the atomistic or quantum level. In this study, we attempt a top-down approach and use deep learning methods to obtain an energy function by exploiting the large amount of experimental data acquired with years in the field of structural biology. The energy function is represented by a probability density model learned from a large repertoire of building blocks representing local clusters of amino acids paired with their sequence signature. We demonstrated the feasibility of this approach by generating a neural network energy function and testing its validity on several applications such as discriminating decoys, assessing qualities of structural models, sampling structural conformations, and designing new protein sequences. We foresee that, in the future, our methodology could exploit the continuously increasing availability of experimental data and simulations and provide a new method for the parametrization of protein energy functions.