Artificial Intelligence Resolves Kinetic Pathways of Magnesium Binding to RNA.

Nadine Schwierz,Jan Neumann

doi:10.1021/acs.jctc.1c00752

Abstract

Magnesium is an indispensable cofactor in countless vital processes. In order to understand its functional role, the characterization of the binding pathways to biomolecules such as RNA is crucial. Despite the importance, a molecular description is still lacking since the transition from the water-mediated outer-sphere to the direct inner-sphere coordination is on the millisecond time scale and therefore out of reach for conventional simulation techniques. To fill this gap, we use transition path sampling to resolve the binding pathways and to elucidate the role of the solvent in the binding process. The results reveal that the molecular void provoked by the leaving phosphate oxygen of the RNA is immediately filled by an entering water molecule. In addition, water molecules from the first and second hydration shell couple to the concerted exchange. To capture the intimate solute–solvent coupling, we perform a committor analysis as the basis for a machine learning algorithm that derives the optimal deep learning model from thousands of scanned architectures using hyperparameter tuning. The results reveal that the properly optimized deep network architecture recognizes the important solvent structures, extracts the relevant information, and predicts the commitment probability with high accuracy. Our results provide detailed insights into the solute–solvent coupling which is ubiquitous for kosmotropic ions and governs a large variety of biochemical reactions in aqueous solutions.

Highlights

Magnesium plays a vital role in almost every biological process
More than 800 different biochemical roles of Mg2+ have been identified in physiological processes ranging from the creation of cellular energy or the synthesis of biomolecules to the activation of enzymes and ribozymes.[1−5] The specific requirement for Mg2+ as a cofactor is pronounced in nucleic acid systems where Mg2+ plays structural roles by complexing negatively charged groups or catalytic roles by accelerating or inhibiting chemical reactions in ribozymes.[3,6−8] In RNA systems, Mg2+ ions are essential for two reasons: They screen the electrostatic repulsion, allowing RNA to fold into compact and functional structures.[9]
The second reason why cations are essential is that binding of Mg2+ to active binding sites allows ribozymes to perform chemical reactions that would not be possible from the basic RNA building blocks alone.[3,6]

Summary

Introduction

In RNA systems, Mg2+ ions are essential for two reasons: They screen the electrostatic repulsion, allowing RNA to fold into compact and functional structures.[9] In addition, a smaller fraction of Mg2+ ions interacts directly with the functional atom groups of the RNA These site-specific ions stabilize the three-dimensional structure further and are involved either in a direct contact (inner-sphere) or are mediated through the hydrogen bond of a coordinating water molecule (solvent-shared).[7,9] The second reason why cations are essential is that binding of Mg2+ to active binding sites allows ribozymes to perform chemical reactions that would not be possible from the basic RNA building blocks alone.[3,6]. As a first step in providing a thorough understanding, we here resolve the binding pathways of Mg2+

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Results

Conclusion