Molecular Modeling of Nucleic Acid Structure: Setup and Analysis

Abstract

The last in a set of units by these authors, this unit addresses some important remaining questions about molecular modeling of nucleic acids. It describes how to choose an appropriate molecular mechanics force field; how to set up and equilibrate the system for accurate simulation of a nucleic acid in an explicit solvent by molecular dynamics or Monte Carlo simulation; and provides some information about how to analyze molecular dynamics trajectories. ISSUES WITH SIMULATING NUCLEIC ACIDSFrom the information presented in previous units (UNITS 7.5, 7.8 & 7.9), one should have a reasonable understanding of the various trade-offs that are necessary to model nucleic acid structures. For instance, when choosing an energy representation and a means to sample relevant conformations, there is a tradeoff between detail, sampling, and computational cost. Although the discussions thus far have presented basic means for modeling nucleic acids, some important details have not been sufficiently addressed. Reasonable decisions that remain for the prospective modeler to address are: (1) which empirical molecular mechanical force field is appropriate; (2) if one wants to run an accurate simulation of a nucleic acid in an explicit solvent, how does one set up and equilibrate the system; (3) how long should the production time of the simulation be in order to see convergence in properties of interest; and (4) how does one analyze molecular dynamics trajectories? This unit provides the answers to some of these questions and outlines a protocol for accurate simulation of nucleic acids.

Binding Dynamics of siRNA with Selected Lipopeptides: A Computer-Aided Study of the Effect of Lipopeptides’ Functional Groups and Stereoisomerism

“…The box dimensions were set to ensure at least 3 nm thickness for the solvent surrounding the LP–siRNA system in all directions. This value is well above the minimum value of 0.8–1.2 nm recommended in current protocols for nucleic acids simulations . Furthermore, it ensures both the presence of the hydration shell, identifiable in the double stranded nucleic acids, and the necessary amount of surrounding bulk water .…”

“…1.2 nm recommended in current protocols for nucleic acids simulations. 59 Furthermore, it ensures both the presence of the hydration shell, identifiable in the double stranded nucleic acids, and the necessary amount of surrounding bulk water. 60 The total number of water molecules in the box was over 73 600 for the largest system of this study (LP:siRNA at the ratio of 8:1).…”

Deformability Calculation for Estimation of the Relative Stability of Chemically Modified RNA Duplexes

“…As mentioned in the previous section, general protocols for MD simulations have been reported (UNIT 7.10; Galindo-Murillo et al, 2014). In addition, detailed tutorials are provided on the AMBER Web site (Tutorial B1).…”

Stability and repair of DNA adducts formed by food-borne alkenylbenzene liver carcinogens; consequences for hazards and risks

“…The choice of a force field can always be debated. There are three force fields for nucleic acids that are frequently applied: the AMBER ff9x, CHARMM c36, and GROMOS force fields (Galindo-Murillo et al 2014). In a recent study, using the AMBER force field, including the bsc1 and OL15 modifications, simulations with longer simulation time could not provide a satisfactory description of the transitions of double-stranded DNA between the A-and B-forms, resulting in too many states of the DNA in B type geometry and basically the absence of the A type geometry (Zgarbová et al 2018).…”

“…In the current thesis, the GROMOS force field was used. Different from the AMBER and CHARMM force fields, this force field can provide more flexibility of the DNA due to the limited Watson-Crick hydrogen bonding (Galindo-Murillo et al 2014). The limited Watson-Crick hydrogen bonding also induces issues with terminal base pair fraying followed by distortion of the whole structure (Ricci et al 2010;Setz 2018).…”