Molecular dynamics simulations of G-quadruplexes: The basic principles and their application to folding and ligand binding

Jiri Sponer, Barira Islam, Petr Stadlbauer, Shozeb Haider

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Current state-of-the art explicit-solvent atomistic molecular dynamics (MD) simulations are reviewed. We describe the basic principles and limitations of MD methodology. We also explain how to compare MD simulations with experiments and how to correctly interpret MD data. Different types of simulation approaches are introduced. We start with standard simulations and then continue with techniques which allow one to a certain extent overcome sampling limitations and derive free energies: replica-exchange methods, collective-variable based methods such as metadynamics, alchemical methods, Markov state models and continuum solvent approach. We emphasize explaining the limitations of the methods, in order to avoid over-interpretation of the simulation data. Then we introduce recent progress in the force fields that are used for simulations of quadruplexes. Finally, two specific areas are reviewed. First, we explain how MD simulations are essential to unravel the uniqueness and complexity of quadruplex folding landscape, what are the basic consequences and hallmarks of kinetic partitioning of the landscape and why low-dimensionality descriptions (both experimental and computational) can easily lead to major oversimplifications. Second, MD simulations-based recent approaches to probe quadruplex-ligand interactions are discussed. The review is primarily written for readers who are not advanced experts in MD simulations, with the aim to openly expose their limitations.

Original languageEnglish
Title of host publicationQuadruplex Nucleic Acids As Targets For Medicinal Chemistry
EditorsStephen Neidle
PublisherAcademic Press Inc.
Chapter7
Pages197-241
Number of pages45
Volume54
Edition1st
ISBN (Print)9780128210178
DOIs
Publication statusPublished - 25 Aug 2020

Publication series

NameAnnual Reports in Medicinal Chemistry
PublisherElsevier
Volume54
ISSN (Print)0065-7743

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    Sponer, J., Islam, B., Stadlbauer, P., & Haider, S. (2020). Molecular dynamics simulations of G-quadruplexes: The basic principles and their application to folding and ligand binding. In S. Neidle (Ed.), Quadruplex Nucleic Acids As Targets For Medicinal Chemistry (1st ed., Vol. 54, pp. 197-241). (Annual Reports in Medicinal Chemistry; Vol. 54). Academic Press Inc.. https://doi.org/10.1016/bs.armc.2020.04.002