Studying the Dynamics of a Complex G-Quadruplex System: Insights into the Comparison of MD and NMR Data

[Image: see text] Molecular dynamics (MD) simulations are coming of age in the study of nucleic acids, including specific tertiary structures such as G-quadruplexes. While being precious for providing structural and dynamic information inaccessible to experiments at the atomistic level of resolution, MD simulations in this field may still be limited by several factors. These include the force fields used, different models for ion parameters, ionic strengths, and water models. We address various aspects of this problem by analyzing and comparing microsecond-long atomistic simulations of the G-quadruplex structure formed by the human immunodeficiency virus long terminal repeat (HIV LTR)-III sequence for which nuclear magnetic resonance (NMR) structures are available. The system is studied in different conditions, systematically varying the ionic strengths, ion numbers, and water models. We comparatively analyze the dynamic behavior of the G-quadruplex motif in various conditions and assess the ability of each simulation to satisfy the nuclear magnetic resonance (NMR)-derived experimental constraints and structural parameters. The conditions taking into account K(+)-ions to neutralize the system charge, mimicking the intracellular ionic strength, and using the four-atom water model are found to be the best in reproducing the experimental NMR constraints and data. Our analysis also reveals that in all of the simulated environments residues belonging to the duplex moiety of HIV LTR-III exhibit the highest flexibility.