Abstract:Structure and deformability of the DNA double helix play a key role in protein and small ligand binding, in genome regulation via looping, or in nanotechnology applications. Here we review some of the recent developments in modeling mechanical properties of DNA in its most common B-form. We proceed from atomic-resolution molecular dynamics (MD) simulations through rigid base and base-pair models, both harmonic and multistate, to rod-like descriptions in terms of persistence length and elastic constants. The re… Show more
“…denoting equilibrium averages, so that ∆ n = 0. Small deformations from equilibrium are usually described within the harmonic approximation 2 , with an energy given by…”
We investigate the mechanical properties of double stranded RNA by means of all-atom simulations and compare its elastic behavior to that of DNA. Differently from DNA, which is characterized by a strong coupling between twist and roll degrees of freedom, such coupling is very weak in RNA. Both nucleic acids are characterized by couplings between distal sites, i.e.\ by interactions that go beyond nearest neighbors. These non-local couplings, both in RNA and DNA, are strong for tilt and twist degrees of freedom and weak for roll. We introduce and analyze a simple double stranded polymer model which clarifies the origin of the distal couplings. Overall, our results indicate that nucleic acid mechanics is well-described by a non-local Twistable Worm Like Chain (nlTWLC). Differently from its local counterpart, the nlTWLC is characterized by a length-scale-dependent elasticity: nucleic acids are mechanically softer at the scale of a few base pairs as compared to an asymptotic stiffer behavior.
“…denoting equilibrium averages, so that ∆ n = 0. Small deformations from equilibrium are usually described within the harmonic approximation 2 , with an energy given by…”
We investigate the mechanical properties of double stranded RNA by means of all-atom simulations and compare its elastic behavior to that of DNA. Differently from DNA, which is characterized by a strong coupling between twist and roll degrees of freedom, such coupling is very weak in RNA. Both nucleic acids are characterized by couplings between distal sites, i.e.\ by interactions that go beyond nearest neighbors. These non-local couplings, both in RNA and DNA, are strong for tilt and twist degrees of freedom and weak for roll. We introduce and analyze a simple double stranded polymer model which clarifies the origin of the distal couplings. Overall, our results indicate that nucleic acid mechanics is well-described by a non-local Twistable Worm Like Chain (nlTWLC). Differently from its local counterpart, the nlTWLC is characterized by a length-scale-dependent elasticity: nucleic acids are mechanically softer at the scale of a few base pairs as compared to an asymptotic stiffer behavior.
“…MD simulations are widely used to study the structure and dynamics of dsDNA and other nucleic acids. It is possible to reproduce the dynamics and deformability of B-DNA (in also other regular forms of DNA) in quite good agreement with available experimental data. − However, so far, only very few simulation studies on ssDNA or folding of DNA structural motifs and on the process of dsDNA structure formation have been performed. An important prerequisite for successful simulations of dsDNA formation but also folding of more complicated DNA structures is a realistic description of nearest-neighbor effects in the underlying force field.…”
The thermodynamic
stability of double-stranded (ds)DNA depends
on its sequence. It is influenced by the base pairing and stacking
with
neighboring bases along DNA molecules. Semiempirical schemes are available
that allow us to predict the thermodynamic stability of DNA sequences
based on empirically derived nearest-neighbor contributions of base
pairs formed in the context of all possible nearest-neighbor base
pairs. Current molecular dynamics (MD) simulations allow one to simulate
the dynamics of DNA molecules in good agreement with experimentally
obtained structures and available data on conformational flexibility.
However, the suitability of current force field methods to reproduce
dsDNA stability and its sequence dependence has been much less well
tested. We have employed alchemical free-energy simulations of whole
base pair transversions in dsDNA and in unbound single-stranded partner
molecules. Such transversions change the sequence context but not
the nucleotide content or base pairing in dsDNA and allow a direct
comparison with the empirical nearest-neighbor dsDNA stability model.
For the alchemical free-energy changes in the unbound single-stranded
(ss)DNA partner molecules, we tested different setups assuming either
complete unstacking or unrestrained simulations with partial stacking
in the unbound ssDNA. The free-energy simulations predicted nearest-neighbor
effects of similar magnitude, as observed experimentally but showed
overall limited correlation with experimental data. An inaccurate
description of stacking interactions and other possible reasons such
as the neglect of electronic polarization effects are discussed. The
results indicate the need to improve the realistic description of
stacking interactions in current molecular mechanic force fields.
“…Recently and thanks to the effort of the community, MD models has proven also powerful in quantitatively reproducing the conformations dynamics and mechanical response of DNA and RNA [65,66,67,15,68,69,70,71] (see section 3). This section shows how MD provides molecular insight into the interactions of RNA with ions.…”
Section: Rna Electrostatics At the Atomic Level: The Importance Of Th...mentioning
Multiscale simulations have broadened our understanding of RNA structure and function. Various methodologies have enabled the quantification of electrostatic and mechanical interactions of RNA at the nanometer scale. Atom-by-atom simulations, coarse-grained strategies, and continuum models of RNA and its environment provide physical insight and allow to interpret diverse experiments in a systematic way. In this chapter, we present and discuss recent advances in a set of methods to study nucleic acids at different scales. In particular, we introduce details of their parameterization, recent applications, and current limitations. We discuss the interaction of the proteinacous virus capsid, RNA with substrates, compare the properties of RNA and DNA and their interaction with the environment, and analyze the application of these methods to reconstruct the structure of the virus genome structure. Finally, the last lines are dedicated to future developments and challenges ahead.
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