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. 2022 Jul 12;18(7):4515-4528.
doi: 10.1021/acs.jctc.2c00291. Epub 2022 Jun 6.

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

Matteo Castelli  1 , Filippo Doria  1 , Mauro Freccero  1 , Giorgio Colombo  1   2 , Elisabetta Moroni  2
Affiliations

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

Matteo Castelli et al. J Chem Theory Comput. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Comparison of HIV LTR-III (a) with minimal G-quadruplex molecular structure (b) (PDB: 3CDM) to provide a pictorial view of the complexity of LTR-III compared to simpler, classical G4 structures.
Figure 2
Figure 2
Schematic representation of a generalized inclusive mechanism of K+ in the G4 central cavity. Representative frames derive from KCl-TIP4P replica-2. (a) First approach of K+ to G4 (at 3 ns), (b) temporary placement of K+ (at 4.18 ns), (c) stable positioning of K+ between two tetrad planes (at 4.19 ns), (d) approach of a second K+ (at 18.1 ns), and (e) stable arrangement with two included K+ in the central cavity (at 91.28 ns).
Figure 3
Figure 3
SDFs of K+-ions around the most populated cluster for each simulation environment (for detail, see Figure 7). Ion distribution is calculated through a 3D grid and normalized by density (default particle density for water based on 1.0 g/mL). Higher values represent a more stable presence of K+-ions. Regions in red represent values larger than 1, while blue regions are referred to values between 0 and 1.
Figure 4
Figure 4
Simplified scheme of water exclusion from the G4 cavity due to the entry of ions. (a) The first approach of K+ with the subsequent water exit from the G4 channel; (b) approach of the second K+ from the opposite side of the G4; exclusion of the second water molecule; and (c) stable arrangement with two included K+ in the central cavity.
Figure 5
Figure 5
Time evolution of RMSD of the G4 nucleobase atomic position from the 10 structures of NMR bundle during simulation with different solvent environments: (a) K-TIP3P, (b) K-TIP4P, (c) KCl-TIP3P, and (d) KCl-TIP4P.
Figure 6
Figure 6
RMSFs of all atomic positions calculated with respect to the averaged structure of each system. Duplex residues are reported in green, G4 in red, and the other in black.
Figure 7
Figure 7
Clustering calculations were carried out to highlight duplex twisting. Trajectories were aligned over the G4, and clustering was focused on the duplex. (a) Different conformations are superimposed to reach 80% representativeness of the system. (b) All-atom root-mean-square deviations (RMSDs) were calculated with respect to the most populated conformation of each environment. (c) Duplex RMSDs were calculated with respect to the most populated conformation of each environment.
Figure 8
Figure 8
(a) Schematic representation of NOE violations. Residue dimension is directly proportional to the number of violations. (b) Histogram representing the number of violations per residues with different solvent environments.
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