The Effect of the Ala16Val Mutation on the Secondary Structure of the Manganese Superoxide Dismutase Mitochondrial Targeting Sequence

Abstract

Manganese Superoxide Dismutase (MnSOD) represents a mitochondrial protein that scavenges reactive oxygen species (ROS) responsible for oxidative stress. A known single nucleotide polymorphism (SNP) rs4880 on the SOD2 gene, causing a mutation from alanine to valine (Ala16Val) in the primary structure of immature MnSOD, has been associated with several types of cancer and other autoimmune diseases. However, no conclusive correlation has been established yet. This study aims to determine the effect of the alanine to valine mutation on the secondary structure of the MnSOD mitochondrial targeting sequence (MTS). A model for each variant of the MTS was prepared and extensively simulated with molecular dynamics simulations using the CHARMM36m force field. The results indicate that the alanine variant of the MTS preserves a uniform α-helical secondary structure favorable for the protein transport into mitochondria, whereas the valine variant quickly breaks down its α-helix. Thus, the alanine MTS represents the more active MnSOD variant, the benefits of which have yet to be determined experimentally.

Naive Prediction of Protein Backbone Phi and Psi Dihedral Angles Using Deep Learning

“…Moreover, a correlation study was conducted on eleven further experimental systems. These included a small well-described system (PDB ID: 1CRN [55]; Figure S5), a large system of Salinosporamide A complexed with yeast 20S proteasome (PDB ID: 2FAK [56]; Figure S6), homodimeric hemoglobin (PDB ID: 3QOB [57], Figure S7), a mediumsized system E. Coli DNA gyrase subunit B (PDB ID: 4DUH [58]; Figure S8), IFN alpha8 (PDB ID: 6JHD [59]; Figure S9), crystal structure of HL homo-diabody (PDB ID: 6KR0 [60]; Figure S10), a cryo-EM structure of the human PA200 and PA200-20S complex (PDB ID: 6KWY [61]; Figure S11), S109 in complex with CRM1-Ran-RanBP1 (PDB ID: 6LQ9 [62]; Figure S12), and a structure of NHP D11A.F2 Fab (PDB ID: 6XLZ [63]; Figure S13), as well as both Ala and Val MnSOD models (Figures S14 and S15), based on the X-ray diffraction by Azadmanesh, et al [64] and studied by Broz et al [65]. All model predictions exhibit MAE values similar to the test dataset predictions, ranging from 12.24 • to 28.26 • for φ errors and from 16.70 • to 77.66 • for ψ errors (Table S3), and the I model could generally classify the correct secondary structure.…”