11.2. Molecular dynamics of protein folding under the influence of external magnetic fields

Project management: Prof. Dr. Ulrich Kleinekathöfer, Jacobs University Bremen
Start: 9 May 2022
End: 9 May 2025

Background

Possible health effects of exposure to low-frequency magnetic fields (MF) have been intensively studied for decades. In 2002, the IARC rated low-frequency MF as “possibly carcinogenic” ^[1]. In a systematic review and meta-analysis ^[2], an increased risk for the occurrence of amyotrophic lateral sclerosis (ALS) was observed in occupationally exposed populations. The occurrence of ALS is associated with the misfolding of certain proteins (e.g. TAR-DNA binding protein 43 (TDP-43) or Cu/Zn superoxide dismutase (SOD1)) ^[3]. Furthermore, a modification of the calmodulin (CaM) activation by external static MF was observed ^[4]. These and other examples suggest the unconfirmed assumption that external MF could influence the long-term dynamics of certain proteins. However, a mechanism of action that could explain low-frequency MF as the cause of the observed effects cannot be deduced from the aforementioned studies. This requires the identification of the underlying field–molecule interactions and, based on this, an investigation of the time evolution of a biopolymer under the influence of the external field. Because of the enormous size of biopolymers and their environment, this is numerically possible only with enormous computational effort. The research uses molecular dynamics (MD) simulation for this purpose: With the help of a numerical algorithm (e.g. velocity Verlet ^[5]), the classical Newtonian equations of motion of the system are solved in finite time intervals under a stochastic noise background.

For electromagnetic fields, it is particularly interesting that external fields can be taken into account by modifying the underlying force fields. This was done in the area of electric fields, for example in ^{[6, 7]}_.

In the case of MF, the integration into the numerical algorithms took place only in recent years. This makes use of the fact that moving charged particles in an MF experience the Lorentz force. The implementation in the velocity Verlet code and first results were achieved in ^{[8, 9]}.

This opens up the promising perspective of investigating the effects of external MF on the aforementioned proteins or certain sub-proteins in order to identify misfoldings or to detect corresponding signs in the free energy landscape of the respective multi-particle system, amongst other things.

Objective

The aim of the project is the molecular simulation of the influence of external MF on proteins and especially their folding. Both biologically relevant realistic systems and model peptides will be investigated. The evaluation of the trajectories obtained with regard to specific physical parameters such as RMSD values, gyration radii, and charge and surface distributions as well as dipole moment spectra should provide information about the temporal development of the conformation of the systems involved.

Implementation

On specially selected protein structures (on the one hand, large, biologically relevant systems; on the other hand, small model peptides for long-term simulations), fully atomistic MD simulations will be carried out with the NAMD program. In addition to “free” protein folding simulations, force-driven MD simulations are performed. The methods used include accelerated molecular dynamics, bias functional, and replica exchange simulations. The numerically complex and time-consuming trajectory calculations are performed on a graphically accelerated computer. For each system, several trajectories with and without external field are compared with each other.

The evaluation of the simulations is done in a first step by MD standard analyses. These include the investigation of the time evolution of the relative position of the system with respect to its mean value (RMSD value) and the gyration radii, the investigation of the hydrophobic/hydrophilic surfaces, the dipole moment spectrum, and the electric charge distributions. By repeating the analyses on several trajectories with and without external field, the aim is to work out differences in a statistically significant manner. Finally, in a second step, the relevance with regard to radiation protection is assessed, and threshold values of the field strengths below which effects on the physical parameters described above can be excluded within the framework of the simulations carried out are determined.

References

1 International Agency for Research on Cancer, 2002. Non-ionizing radiation (Vol. 80). World Health Organization.

2 Huss, A., Peters, S. and Vermeulen, R., 2018. Occupational exposure to extremely low‐frequency magnetic fields and the risk of ALS: A systematic review and meta‐analysis. Bioelectromagnetics, 39(2), pp.Lit 2 156-163.

3 McAlary, L., Plotkin, S.S., Yerbury, J.J. and Cashman, N., 2019. Prion-like propagation of protein misfolding and aggregation in amyotrophic lateral sclerosis. Frontiers in molecular neuroscience, 12, p.262.

4 Liboff, A.R., Cherng, S., Jenrow, K.A. and Bull, A., 2003. Calmodulin‐dependent cyclic nucleotide phosphodiesterase activity is altered by 20 μT magnetostatic fields. Bioelectromagnetics: Journal of the Bioelectromagnetics Society, The Society for Physical Regulation in Biology and Medicine, The European Bioelectromagnetics Association, 24(1), pp.32-38.

5 Allen, M.P., 2004. Introduction to molecular dynamics simulation. Computational soft matter: from synthetic polymers to proteins, 23(1), pp.1-28.

6 della Valle, E., Marracino, P., Pakhomova, O., Liberti, M. and Apollonio, F., 2019. Nanosecond pulsed electric signals can affect electrostatic environment of proteins below the threshold of conformational effects: The case study of SOD1 with a molecular simulation study. PloS one, 14(8), p.e0221685.

7 Marracino, P., Havelka, D., Průša, J., Liberti, M., Tuszynski, J., Ayoub, A.T., Apollonio, F. and Cifra, M., 2019. Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation. Scientific reports, 9(1), pp.1-14.

8 della Valle, E., Marracino, P., Setti, S., Cadossi, R., Liberti, M. and Apollonio, F., 2017, August. Magnetic molecular dynamics simulations with Velocity Verlet algorithm. In 2017 XXXIInd General Assembly and Scientific Symposium of the International Union of Radio Science (URSI GASS) (pp. 1-4). IEEE.

9 della Valle, E., Marracino, P., Setti, S., Cadossi, R., Liberti, M. and Apollonio, F., 2018, May. Magnetic molecular dynamics simulations of A2A receptor in solution. In 2018 2nd URSI Atlantic Radio Science Meeting (AT-RASC) (pp. 1-3). IEEE.