Molecular Modeling of Nucleic Acid Structure: Electrostatics and Solvation

Abstract

This unit presents an overview of computer simulation techniques as applied to nucleic acid systems, ranging from simple in vacuo molecular modeling techniques to more complete all-atom molecular dynamics treatments that include an explicit representation of the environment. The third in a series of four units, this unit focuses on critical issues in solvation and the treatment of electrostatics. UNITS 7.5 & 7.8 introduced the modeling of nucleic acid structure at the molecular level. This included a discussion of how to generate an initial model, how to evaluate the utility or reliability of a given model, and ultimately how to manipulate this model to better understand the structure, dynamics, and interactions. Subject to an appropriate representation of the energy, such as a specifically parameterized empirical force field, the techniques of minimization and Monte Carlo simulation, as well as molecular dynamics (MD) methods, were introduced as means to sample conformational space for a better understanding of the relevance of a given model. From this discussion, the major limitations with modeling, in general, were highlighted. These are the difficult issues in sampling conformational space effectively-the multiple minima or conformational sampling problems-and accurately representing the underlying energy of interaction. In order to provide a realistic model of the underlying energetics for nucleic acids in their native environments, it is crucial to include some representation of solvation (by water) and also to properly treat the electrostatic interactions. These are discussed in detail in this unit. SubjectNucleic Acid Chemistry; Nucleic Acid Structure and Folding; Structural Analysis of Biomolecules; Experimental Determination of Structure ELECTROSTATICS AND SOLVATIONAccurately modeling the structure and dynamics of nucleic acids with standard ab initio or empirical potentials presents special difficulties due to the highly charged phosphate backbone and the observation that nucleic acids are essentially always hydrated. Even under extremely dehydrating conditions, DNA still has very tightly associated water. To apply an accurate model, some representation of this structural and solvating water is likely necessary. Water has a structural role as both a donor and acceptor of hydrogen bonds, and Internet ResourcesAscona B-DNA Consortium website.

Chemical selectivity of nucleobase adduction relative to in vivo mutation sites on exon 7 fragment of p53 tumor suppressor gene

“…Double stranded DNAs are relatively inflexible due to GC and AT base pairing and double helical structure resulting in their complicated secondary and tertiary structures. 30 The double helical structure also features major and minor groves in duplex DNA. BPDE specifically attacks the electron donating exocyclic amine in the minor groove containing the nucleophilic GC base pair of DNA.…”

“…Further, short strands may exhibit altered structural specificity in nucleophilic addition compared to natural tumor suppressor genes that may show tertiary and quaternary structural influences on codon reactivity. 30 – 34 …”

“…Further, short strands may exhibit altered structural specicity in nucleophilic addition compared to natural tumor suppressor genes that may show tertiary and quaternary structural inuences on codon reactivity. [30][31][32][33][34] In this paper, we report an LC-MS/MS study of ds fragment of 32 bp of p53 gene exon 7, from codon 242 to 253. This fragment exhibits up to 5 reactive hot spots, [13][14][15][16][17] and our work represents metabolite reactivity of a p53 strand (>20 base pairs) with multiple mutation sites.…”

“…The 32 bp fragment was chosen to be long enough to mimic higher order structure-reactivity of DNA. 30 This fragment was reacted with BPDE, the major DNA-reactive metabolite of benzo[a]pyrene, [35][36][37] and then a restriction enzyme was used to cleave the fragment into smaller fragments to enable LC-MS/MS sequencing.…”

Using All-Atom Potentials to Refine RNA Structure Predictions of SARS-CoV-2 Stem Loops

“…Molecular dynamics simulations employing all-atom force fields can be used to predict the time-dependent motions involved in these RNAs [ 17 ], as well as their thermodynamic probabilities for particular conformations, factors which are critical to understanding higher order structure ensembles intended to be used as targets for small molecule drugs. Additionally, the inclusion of explicit water and ions and the implementation of particle mesh Ewald for modeling long-range electrostatic interactions returns results more consistent with experimental data than a continuum representation, or more primitive treatment of electrostatic terms [ 16 , 18 , 19 ].…”