Phenomenological Model for the Efficient General Regulatory Role of Metabolites

There is growing awareness of the potential regulatory role of metabolites and their relevance in metabolic therapy. For example, the metabolites ATP and arginine can regulate the stability of a wide spectrum of proteins. Interestingly, their effective concentrations (millimolar scale) coincide with their physiological concentrations, while they are significantly lower than those of the cosolvents required. In this work, we use molecular dynamics simulations to explore the mechanisms underlying such an efficient general regulatory role. Their preferential binding coefficients across various regions of proteins are calculated separately, revealing a considerable binding preference toward flexible regions. Therefore, the binding behavior of metabolites cannot be simply interpreted by the canonical preferential binding model and should be conceived as a further partition of bound metabolites on the desired region. We further found this intriguing further partition stems from varying dissociation rates of metabolites: they rapidly desorb from undesired nonflexible regions while remaining bound to desired flexible regions. The resulting partition can also be characterized by a Boltzmann-like distribution in a quantitative way. The proposed model about the further partition of bound metabolites can serve as an extension of the preferential binding model to understand the unique binding behavior of metabolites and their remarkable efficiency.