TY - JOUR

T1 - Dynamic properties of SOD1 mutants can predict survival time of patients carrying familial amyotrophic lateral sclerosis

AU - Alemasov, Nikolay A.

AU - Ivanisenko, Nikita V.

AU - Medvedev, Sergey P.

AU - Zakian, Suren M.

AU - Kolchanov, Nikolay A.

AU - Ivanisenko, Vladimir A.

N1 - Publisher Copyright: © 2016 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2017/2/17

Y1 - 2017/2/17

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - hydrogen bonds

KW - molecular dynamics

KW - prediction

KW - SOD1

KW - survival time

KW - water bridges

KW - Prognosis

KW - Humans

KW - Models, Molecular

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Protein Folding

KW - Mutant Proteins

KW - Hydrogen Bonding

KW - Superoxide Dismutase-1/chemistry

KW - Protein Conformation

KW - Mutation

KW - PROTEIN AGGREGATION

KW - ALS PATIENTS

KW - MUTATIONS

KW - BOND

KW - WILD-TYPE

KW - INSTABILITY

KW - VARIANTS

KW - SUPEROXIDE-DISMUTASE GENE

KW - CU-ZN

KW - COMMON

UR - http://www.scopus.com/inward/record.url?scp=84961200982&partnerID=8YFLogxK

U2 - 10.1080/07391102.2016.1158666

DO - 10.1080/07391102.2016.1158666

M3 - Article

C2 - 26919172

AN - SCOPUS:84961200982

VL - 35

SP - 645

EP - 656

JO - Journal of Biomolecular Structure and Dynamics

JF - Journal of Biomolecular Structure and Dynamics

SN - 0739-1102

IS - 3

ER -