RNA-Specific Force Field Optimization with CMAP and Reweighting

Abstract

RNA plays a key role in a variety of cell activities. However, it is difficult to capture its structure dynamics by the traditional experimental methods because of the inherent limitations. Molecular dynamics simulation has become a valuable complement to the experimental methods. Previous studies have indicated that the current force fields cannot accurately reproduce the conformations and structural dynamics of RNA. Therefore, an RNA-specific force field was developed to improve the conformation sampling of RNA. The distribution of ζ/α dihedrals of tetranucleotides was optimized by a reweighting method, and the grid-based energy correction map (CMAP) term was first introduced into the Amber RNA force field of f f 99bsc0χOL3, named f f 99OL3_CMAP1. Extensive validations of tetranucleotides and tetraloops show that f f 99OL3_CMAP1 can significantly decrease the population of an incorrect structure, increase the consistency between the simulation results and experimental values for tetranucleotides, and improve the stability of tetraloops. f f 99OL3_CMAP1 can also precisely reproduce the conformation of a duplex and riboswitches. These findings confirm that the newly developed force field ff 99OL3_CMAP1 can improve the conformer sampling of RNA.

Dynamics of metal binding and mutation in yybP–ykoY riboswitch of Lactococcus lactis

“…For this purposes, MD simulations were applied to the metal-sensing riboswitches employing the most widely used ff99bsc0χOL3 AMBER force field to model and describe RNA topology despite having several reports that the force field was unable to reproduce some tetranucleotides and tetraloops for the conformational features and NMR experimental data, and therefore, a number refinements and optimizations of the force field were suggested. 44 Nevertheless, the data obtained from the simulation was found to be in good agreement with the experimental data reported so far. Furthermore, the application of non-bonded parameter for the manganese and magnesium ions was also found to be compatible as the structural and dynamical properties of the metal-binding sites reproduced well when compared with experimental data based on X-ray crystallography.…”

Balanced Force Field ff03CMAP Improving the Dynamics Conformation Sampling of Phosphorylation Site

“…In this research, our analysis reveals that the vast majority of phosphorylation occurs in the disordered region of the protein, which leads us to consider introducing CMAP energy for dihedral angles to improve the simulation of phosphorylated proteins. CMAP energy has been widely used to simulate disordered proteins [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ] and can also be used to improve the balanced force field for disordered and structural proteins [ 35 ]. We have tried using the balanced force field to simulate phosphorylated proteins with both structured and disordered regions, and indeed the simulation of the modification sites in the disordered region was more accurate than other force field.…”

“…Compared with the ff03 force field, ff03CMAP adds a correction map (CMAP) parameter to adjust the dihedral angle potential energy, which affects the conformation of the proteins in simulation, achieving improvements in the simulation of disordered proteins without affecting the accuracy of folded proteins [ 35 ]. The CMAP method has been widely used to improve the accuracy of force fields [ 36 , 37 ], especially for disordered proteins [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. The solvent model also affects protein conformations in simulations, therefore we also tested two water models of TIP4P-Ew [ 45 ] and TIP4P-D [ 46 ] with the two force fields to show a combination effect on phosphorylated protein simulation.…”

Lone Pair…π Contacts and Structure Signatures of r(UNCG) Tetraloops, Z-Turns, and Z-Steps: A WebFR3D Survey

“…A recent report summarized some of these challenges for RNA tetraloops that could not all be resolved by recent parameterization efforts [ 54 , 55 , 56 , 57 , 58 , 59 ]. The characteristic r(UUCG) native structure is lost in ns to μs standard MD simulations or does not fold correctly because of at least two different effects.…”