Establishing the catalytic and regulatory mechanism of RNA‐based machineries

Abstract

Ribonucleoprotein (RNP)-machineries are comprised of intricate networks of long noncoding RNAs and proteins that allow them to actively participate in transcription, RNA processing, and translation. RNP-machineries thus play vital roles in gene expression and regulation. Recent advances in cryo-EM techniques provided a wealth of near-atomic-level resolution structures setting the basis for understanding how these fascinating multiscale complexes exert their diverse roles. However, these structures represent only isolated snapshots of the plastic and highly dynamic RNPmachineries and are thus insufficient to comprehensively assess their multifaceted mechanisms. In this review, we discuss the role and merit of allatom simulations in disentangling the mechanism of eukaryotic RNA-based machineries responsible for RNA processing. We showcase how all-atom simulations can capture their large-scale functional movements, trace the signaling pathways that are at the root of their massive conformational remodeling, explain recognition mechanisms of specific RNA sequences, and, lastly, unravel the chemical mechanisms underlying the formation of functional RNA strands. Finally, we review the methodological pitfalls and outline future challenges in modeling key functional aspects of these large molecular engines with all-atom simulations. In addition to providing insights into the most basic processes that govern all forms of life, in-depth mechanistic comprehension of RNP-machineries offers a foundation for developing innovative therapeutic strategies against the variety of human diseases linked to deregulated RNA metabolism. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics K E Y W O R D S cryo-EM, molecular dynamics, ribonucleoproteins, RNA catalysis, RNA processing Jure Borišek and Jana Aupič contributed equally to the study.

Cancer-Related Mutations Alter RNA-Driven Functional Cross-Talk Underlying Premature-Messenger RNA Recognition by Splicing Factor SF3b

“…Thus, our study broadens the understanding of the mechanisms underlying mutant-induced aberrant splicing and enlightens the malleability of HEAT-repeat proteins in handling RNA processing in health and diseases. With the SF3b complex being a validated target of splicing modulators, ,− these findings supply intriguing insights and appealing opportunities for correcting SF3b cancer-associated structural/dynamical alterations with small molecules …”

Monovalent Ionic Atmosphere Modulates the Selection of Suboptimal RNA Sequences by Splicing Factors’ RNA Recognition Motifs

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“…At each splicing cycle, the SPL assembles into a series of complexes (E, A, B, B act , B*, C, C*, P, and ILS) varying in their composition and conformation . Upon forming the E and A complexes, the 5′ and 3′ pre-mRNA splicing sites (SS), located at the intron–exon boundaries, are respectively recognized. , …”

Molecular Dynamics Simulations Elucidate the Molecular Basis of Pre-mRNA Translocation by the Prp2 Spliceosomal Helicase

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