Title: Decoding the protein–ligand interactions using parallel graph neural networks

Abstract

Abstract Protein–ligand interactions (PLIs) are essential for biochemical functionality and their identification is crucial for estimating biophysical properties for rational therapeutic design. Currently, experimental characterization of these properties is the most accurate method, however, this is very time-consuming and labor-intensive. A number of computational methods have been developed in this context but most of the existing PLI prediction heavily depends on 2D protein sequence data. Here, we present a novel parallel graph neural network (GNN) to integrate knowledge representation and reasoning for PLI prediction to perform deep learning guided by expert knowledge and informed by 3D structural data. We develop two distinct GNN architectures: $$$$\hbox {GNN}_{\mathrm{F}}$$$$ ${\text{GNN}}_F$ is the base implementation that employs distinct featurization to enhance domain-awareness, while $$$$\hbox {GNN}_{\mathrm{P}}$$$$ ${\text{GNN}}_P$ is a novel implementation that can predict with no prior knowledge of the intermolecular interactions. The comprehensive evaluation demonstrated that GNN can successfully capture the binary interactions between ligand and protein’s 3D structure with 0.979 test accuracy for $$$$\hbox {GNN}_{\mathrm{F}}$$$$ ${\text{GNN}}_F$ and 0.958 for $$$$\hbox {GNN}_{\mathrm{P}}$$$$ ${\text{GNN}}_P$ for predicting activity of a protein–ligand complex. These models are further adapted for regression tasks to predict experimental binding affinities and $$$$\hbox {pIC}_{\mathrm{50}}$$$$ ${\text{pIC}}_{50}$ crucial for compound’s potency and efficacy. We achieve a Pearson correlation coefficient of 0.66 and 0.65 on experimental affinity and 0.50 and 0.51 on $$$$\hbox {pIC}_{\mathrm{50}}$$$$ ${\text{pIC}}_{50}$ with $$$$\hbox {GNN}_{\mathrm{F}}$$$$ ${\text{GNN}}_F$ and $$$$\hbox {GNN}_{\mathrm{P}}$$$$ ${\text{GNN}}_P$ , respectively, outperforming similar 2D sequence based models. Our method can serve as an interpretable and explainable artificial intelligence (AI) tool for predicted activity, potency, and biophysical properties of lead candidates. To this end, we show the utility of $$$$\hbox {GNN}_{\mathrm{P}}$$$$ ${\text{GNN}}_P$ on SARS-Cov-2 protein targets by screening a large compound library and comparing the prediction with the experimentally measured data.

Authors:

Knutson, Carter; Bontha, Mridula; Bilbrey, Jenna A.; Kumar, Neeraj

Publication Date:

2022-05-10

Research Org.:

Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Sponsoring Org.:

USDOE

OSTI Identifier:

1867072

Alternate Identifier(s):

OSTI ID: 1869774

Report Number(s):

PNNL-SA-166075
Journal ID: ISSN 2045-2322; 7624; PII: 10418

Grant/Contract Number:  

AC05-76RL01830

Resource Type:

Published Article

Journal Name:

Scientific Reports

Additional Journal Information:

Journal Name: Scientific Reports Journal Volume: 12 Journal Issue: 1; Journal ID: ISSN 2045-2322

Publisher:

Nature Publishing Group

Country of Publication:

United Kingdom

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; computational biophysics; screening; viral infection