PNNL

Abstract

Thermodynamics plays a crucial role in regulating the metabolic processes in all living organisms. Accurate determination of thermodynamical properties is important to understand, analyze, and synthetically design such metabolic processes for engineered systems. In this work, we extensively performed first principle quantum mechanical calculations to assess accuracy in estimating free energy of biochemical reactions. We benchmark the quantum chemistry methods based on density functional theory (DFT) against different basis sets, solvation models, temperature, pH, and exchange correlation functionals. Our results show that quantum chemistry calculations when combined with simple calibration yields mean absolute error in the range 1.47-2.13 kcal/mol for different exchange correlation functionals, with SCAN being most accurate with and without calibration. This accuracy over a diverse set of metabolic reactions is unprecedented and near the benchmark chemical accuracy of 1 kcal/mol that is usually desired from DFT calculations. We also evaluated the performance of the QC method with respect to charges on metabolites to better understand its role on the thermodynamics o. Furthermore, the automated computational pipeline built for this work has been integrated as a narrative in the DOE Systems Biology Knowledgebase (KBase) that can efficiently predict the thermodynamic parameters of biochemical reactions with the most accurate quantum chemical methods.