Dynamic properties of SOD1 mutants can predict survival time of patients carrying familial amyotrophic lateral sclerosis

Abstract

One of the reasons for the death of motor neurons of the brain and spinal cord in patients with amyotrophic lateral sclerosis is known to be formation of subcellular protein aggregates that are caused by mutations in the SOD1 gene. Patient survival time was earlier shown to have limiting correlation with thermostability change of SOD1 mutant forms of patients’ carriers. We hypothesized that aggregation of mutant SOD1 may occur not only due to the protein destabilization, but through formation of novel interatomic bonds which stabilize “pathogenic” conformations of the mutant as well. To estimate these effects in the present paper, we performed statistical analysis of occupancy of intramolecular hydrogen bonds, hydrogen bonds between the protein and water molecules, and water bridges with use of molecular dynamics simulation for 38 mutant SOD1 forms. Multiple regression model based on these kinds of bonds demonstrated correlation with patient survival time significantly better (R = .9, p-value < 10⁻¹¹) than the thermostability of SOD1 mutants only. It was shown that the occupancy of intramolecular hydrogen bonds between amino acid residues is a key determinant (R = .89, p-value < 10⁻¹⁰) in predicting patients’ survival time.

Keywords:

• SOD1
• amyotrophic lateral sclerosis
• molecular dynamics
• hydrogen bonds
• water bridges
• prediction
• survival time

Acknowledgments

High-performance computations and MD simulation were performed based on the “Bioinformatics” center with support of budget project 0324-2015-0003. Implementation of the method for analyzing hydrogen bonds network as well as constructing regression models associating microscopic properties of the SOD1 with its macroscopic ones were carried out under support of Russian scientific foundation grant No. 14-24-0123. Access to the Gaussian software package was provided by Siberian Supercomputer Center.