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Coarse-Grained Simulation of Rodlike Higher-Order Quadruplex Structures at Different Salt Concentrations.

ABSTRACT: We present a coarse-grained (CG) model of a rodlike higher-order quadruplex with explicit monovalent salts, which was developed from radial distribution functions of an underlying reference atomistic molecular dynamics simulation using inverse Monte Carlo technique. This work improves our previous CG model and extends its applicability beyond the minimal salt conditions, allowing its use at variable ionic strengths. The strategies necessary for the model development are clearly explained and discussed. The effects of the number of stacked quadruplexes and varied salt concentration on the elasticity of the rodlike higher-order quadruplex structures are analyzed. The CG model reproduces the deformations of the terminal parts in agreement with experimental observations without introducing any special parameters for terminal beads and reveals slight differences in the rise and twist of the G-quartet arrangement along the studied biopolymer. The conclusions of our study can be generalized for other G-quartet-based structures.

SUBMITTER: Rebic M

PROVIDER: S-EPMC6641151 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Coarse-Grained Simulation of Rodlike Higher-Order Quadruplex Structures at Different Salt Concentrations.

Rebič Matúš M Mocci Francesca F Uličný Jozef J Lyubartsev Alexander P AP Laaksonen Aatto A

ACS omega 20170203 2

We present a coarse-grained (CG) model of a rodlike higher-order quadruplex with explicit monovalent salts, which was developed from radial distribution functions of an underlying reference atomistic molecular dynamics simulation using inverse Monte Carlo technique. This work improves our previous CG model and extends its applicability beyond the minimal salt conditions, allowing its use at variable ionic strengths. The strategies necessary for the model development are clearly explained and dis ...[more]

PMID: 31457446

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Project description:Protamine, a small, strongly positively-charged protein, plays a key role in achieving chromatin condensation inside sperm cells and is also involved in the formulation of nanoparticles for gene therapy and packaging of mRNA-based vaccines against viral infection and cancer. The detailed mechanisms of such condensations are still poorly understood especially under low salt conditions where electrostatic interaction predominates. Our previous study, with a refined coarse-grained model in full consideration of the long-range electrostatic interactions, has demonstrated the crucial role of electrostatic interaction in protamine-controlled reversible DNA condensation. Therefore, we herein pay our attention only to the electrostatic interaction and devise a coarser-grained bead-spring model representing the right linear charge density on protamine and DNA chains but treating other short-range interactions as simply as possible, which would be suitable for real-scale simulations. Effective pair potential calculations and large-scale molecular dynamics simulations using this extremely simple model reproduce the phase behaviour of DNA in a wide range of protamine concentrations under low salt conditions, again revealing the importance of the electrostatic interaction in this process and providing a detailed nanoscale picture of bundle formation mediated by a charge disproportionation mechanism. Our simulations also show that protamine length alters DNA overcharging and in turn redissolution thresholds of DNA condensates, revealing the important role played by entropies and correlated fluctuations of condensing agents and thus offering an additional opportunity to design tailored nanoparticles for gene therapy. The control mechanism of DNA-protamine condensates will also provide a better microscopic picture of biomolecular condensates, i.e., membraneless organelles arising from liquid-liquid phase separation, that are emerging as key principles of intracellular organization. Such condensates controlled by post-translational modification of protamine, in particular phosphorylation, or by variations in protamine length from species to species may also be responsible for the chromatin-nucleoplasm patterning observed during spermatogenesis in several vertebrate and invertebrate species.

Dataset Information

Coarse-Grained Simulation of Rodlike Higher-Order Quadruplex Structures at Different Salt Concentrations.

Publications

Coarse-Grained Simulation of Rodlike Higher-Order Quadruplex Structures at Different Salt Concentrations.

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