Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
J Biomol Struct Dyn ; 38(3): 647-659, 2020 02.
Article in English | MEDLINE | ID: mdl-30806161

ABSTRACT

Dynamic nature of structural segments is a key modulator of protein's intrinsic stability. Mutants of superoxide dismutase 1 (SOD1) protein, like SOD1G85R and SOD1G93A, adopt misfolded states that undergo aggregation in motor neuron cells. In this study, we had used correlative computational studies to investigate the temporal flux of structural alterations in SOD1G85R and SOD1G93A that increased the instability and aggregation tendency of these proteins. Molecular dynamics simulation studies showed that the G85R and G93A mutations caused localized transitions of the edge-strands of beta sheets to disordered structures near the mutation regions. Though this structural perturbation did not alter the conformation of the catalytic zinc and copper binding residues, it could dislocate the electrostatic loop of SOD1G85R. This had rendered the electrostatic loop of SOD1G85R to be incapable of guiding the substrate to the catalytic cleft. The beta sheet-to-disorder transitions near the mutations had caused the induction of steric clashes in the edge-strand residues, resulting in the loss of several intra-molecular interactions in the mutant SOD1 proteins. These had effected in local structural destabilization and increased aggregation potential in SOD1G85R and SOD1G93A. Mutant SOD1 proteins adopted energetically less favorable states, with some changes in the residue-level conformation entropy and solvent-exposed surfaces of the mutation neighboring residues. Collectively, our study demonstrated that the two mutations, G85R and G93A, did not have global effects in changing the SOD1 structure. Instead, the instability-associated aggregation of these mutants arose due to the local structural alterations in the edge-strands of specific beta sheets.Communicated by Ramaswamy H. Sarma.


Subject(s)
Mutant Proteins/chemistry , Mutant Proteins/metabolism , Protein Aggregates , Protein Folding , Superoxide Dismutase-1/chemistry , Superoxide Dismutase-1/metabolism , Biocatalysis , Enzyme Stability , Mutation/genetics , Protein Conformation, beta-Strand , Superoxide Dismutase-1/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...