Exploring the RNA-Recognition Mechanism Using Supervised Molecular Dynamics (SuMD) Simulations: Toward a Rational Design for Ribonucleic-Targeting Molecules?

Maicol Bissaro,Mattia Sturlese,Stefano Moro

doi:10.3389/fchem.2020.00107

Abstract

Although proteins have represented the molecular target of choice in the development of new drug candidates, the pharmaceutical importance of ribonucleic acids has gradually been growing. The increasing availability of structural information has brought to light the existence of peculiar three-dimensional RNA arrangements, which can, contrary to initial expectations, be recognized and selectively modulated through small chemical entities or peptides. The application of classical computational methodologies, such as molecular docking, for the rational development of RNA-binding candidates is, however, complicated by the peculiarities characterizing these macromolecules, such as the marked conformational flexibility, the singular charges distribution, and the relevant role of solvent molecules. In this work, we have thus validated and extended the applicability domain of SuMD, an all-atoms molecular dynamics protocol that allows to accelerate the sampling of molecular recognition events on a nanosecond timescale, to ribonucleotide targets of pharmaceutical interest. In particular, we have proven the methodological ability by reproducing the binding mode of viral or prokaryotic ribonucleic complexes, as well as that of artificially engineered aptamers, with an impressive degree of accuracy.

Highlights

Ribonucleic acid (RNA) is a polymer whose biological importance has increased progressively over the last 50 years
Molecular dynamics (MD) simulations were performed with an ACEMD engine (Harvey et al, 2009) on a GPU cluster composed of 18 NVIDIA drivers whose models go from GTX 980 to Titan V
The ff14SB force field with χ modification tuned for RNA was adopted to describe ribonucleic acids, while a general Amber force field (GAFF) was adopted to parameterize small organic molecules (Wang et al, 2006; Sprenger et al, 2015; Tan et al, 2018)

Summary

Introduction

Ribonucleic acid (RNA) is a polymer whose biological importance has increased progressively over the last 50 years. Despite the central dogma of molecular biology considering this nucleic acid as a functional messenger between DNA genetic information storage and protein biosynthesis, RNA has recently been reappraised as an ancestral molecule of primary importance in the abiogenesis process. At the origin of life, RNA probably encompassed both an informational role, which progressively evolved toward involving the more stable and replicable DNA polymer, and a catalytic function, which was gradually flanked by more versatile proteins. The complexity hiding behind RNA’s biological functions is intuitable by taking into consideration the human organism, which genetic heritage could quite entirely be transcribed into RNA, despite coding only in a minimal portion (about 3%) for proteins (Warner et al, 2018). RNA revolution has shed light on the regulatory activity of this widely different class of macromolecules that, along with some proteins, cooperate to control and finely orchestrate the genome expression (Connelly et al, 2016)

Methods

Results

Conclusion