Molecular dynamics simulations of RNA: An in silico single molecule approach

Abstract

RNA molecules are now known to be involved in the processing of genetic information at all levels, taking on a wide variety of central roles in the cell. Understanding how RNA molecules carry out their biological functions will require an understanding of structure and dynamics at the atomistic level, which can be significantly improved by combining computational simulation with experiment. This review provides a critical survey of the state of molecular dynamics (MD) simulations of RNA, including a discussion of important current limitations of the technique and examples of its successful application. Several types of simulations are discussed in detail, including those of structured RNA molecules and their interactions with the surrounding solvent and ions, catalytic RNAs, and RNA-small molecule and RNA-protein complexes. Increased cooperation between theorists and experimentalists will allow expanded judicious use of MD simulations to complement conceptually related single molecule experiments. Such cooperation will open the door to a fundamental understanding of the structure-function relationships in diverse and complex RNA molecules.

Balance of Attraction and Repulsion in Nucleic-Acid Base Stacking: CCSD(T)/Complete-Basis-Set-Limit Calculations on Uracil Dimer and a Comparison with the Force-Field Description

“…Despite the reported difference we would like to clearly state that the overall description of base stacking and H-bonding by the nonbonded potential of the AMBER force field is good, and, as we pointed out elsewhere, stacking is probably the best approximated term in the force field. 138,139 The discrepancy reported here should not affect the overall stability of the simulations and qualitative applications of the method. However, it may affect the description of very subtle quantitative effects such as the local conformational variations in B-DNA.…”

Geometrical and Electronic Structure Variability of the Sugar−phosphate Backbone in Nucleic Acids

“…This had complicated their simulation for many years. [3][4][5][6][7][8][9][10] Fortunately, progress in the development of simulation methods over the past decade, including the availability of balanced molecular mechanical force fields 11,12 and efficient methods to handle longrange electrostatic interactions, 13,14 has paved the way toward reliable nano-to microsecond simulations of NAs. 15,16 One of the leading force fields for the modeling of NAs has been the Cornell et al ff94 force field 11 and its improved variants ff98 17 and ff99, 1 which are available in the AMBER suite of programs.…”

“…19,20 In spite of some known deficiencies, such as the visible under-twisting of the B-DNA double helix, 6,21 short explicit solvent MD simulations using the AMBER force fields have been rather effectively applied to a variety of systems. [3][4][5][6][7][8][9][10][22][23][24][25][26][27][28][29][30][31][32] The AMBER force fields have also been successful in studies of RNA molecules, including those that exhibit a wide range of non-Watson-Crick base pairings, tertiary interactions, and complex backbone topologies. [33][34][35][36][37][38][39][40][41][42][43] These studies have also emphasized the importance of NAs' sugar-phosphate backbone flexibility, which is delimited by six main-chain torsion angles (designated as R through ), in addition to the five internal sugar torsions (denoted as τ 0 through τ 4 , which can be succinctly described by the puckering and the phase angle 44 ), and the glycosidic angle 45 (see Figure 1).…”

Flexibility of Short-Strand RNA in Aqueous Solution as Revealed by Molecular Dynamics Simulation: Are A-RNA and A´-RNA Distinct Conformational Structures?

“…30,31 Computational studies of DNA and RNA have also been elaborated in the recent book by Sponer and Lankas. 32 In relation to molecular dynamics simulations of RNA specifically, progress made in the last twenty years in this area has been summarized by McDowell et al 33 and by Hashem et al, 34 providing summaries of simulations, force field approximations, RNA interactions with solvents and ions, catalytic RNAs and RNA-protein (or small molecule) complexes. tRNA was the first RNA molecule with an X-ray structure to be studied by MD simulations.…”