Abstract
Thermodynamics dictates the structure and function of metabolism. Redox reactions drive cellular energy and material flow. Hence, accurately quantifying the thermodynamics of redox reactions should reveal design principles that shape cellular metabolism. However, only few redox potentials have been measured, and mostly with inconsistent experimental setups. Here, we develop a quantum chemistry approach to calculate redox potentials of biochemical reactions and demonstrate our method predicts experimentally measured potentials with unparalleled accuracy. We then calculate the potentials of all redox pairs that can be generated from biochemically relevant compounds and highlight fundamental trends in redox biochemistry. We further address the question of why NAD/NADP are used as primary electron carriers, demonstrating how their physiological potential range fits the reactions of central metabolism and minimizes the concentration of reactive carbonyls. The use of quantum chemistry can revolutionize our understanding of biochemical phenomena by enabling fast and accurate calculation of thermodynamic values.
Highlights
In order to understand life we need to understand the forces that support and constrain it
We show that the quantum chemical method can predict experimentally derived reduction potentials with considerably higher accuracy than group contribution method (GCM) when calibrated with only two parameters
We focus on explaining the central role of NAD(P) as electron carrier from the perspective of the redox reactions it supports and the role it plays in lowering the concentration of reactive carbonyls
Summary
In order to understand life we need to understand the forces that support and constrain it. Thermodynamics provides the fundamental constraints that shape metabolism [1,2,3,4,5]. Redox reactions constitute the primary metabolic pillars that support life. Redox biochemistry has shaped the study of diverse fields in biology, including origin-of-life [9], circadian clocks [10], carbon-fixation [11], cellular aging [12], and host-pathogen interactions [13]. Previous work has demonstrated that a quantitative understanding of the thermodynamic parameters governing redox reactions reveals design principles of metabolic pathways. The unfavorable nature of carboxyl reduction and carboxylation explains to a large degree the ATP investment required to support carbon fixation [1]
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