Novel Approaches to Studying Protein Structure/Function Relationships at the Molecular Level

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 1198

Special Issue Editor

Chemistry Department, University of Massachusetts Lowell, Lowell, MA 01854, USA
Interests: protein structure/function; intrinsically disordered proteins; titin; bioinformatics

Special Issue Information

Dear Colleagues,

The question of how a protein’s structure influences its function has been a driving question for nearly as long as the field of protein chemistry has existed. Until the mid-1990s it was believed that function came from ordered structure, but demonstration of the existence of Intrinsically Disordered Proteins (IDPs) has expanded this view. This expanded view of protein structure/function has the driven development of new tools to interrogate function at the molecular level, from an increased number of single-molecule techniques to improved structural techniques such as cryo-EM and time-resolved crystallography. These innovations have provided insights into structure-function relationships that were previously unobtainable. The focus of this Special Issue is to collect articles that highlight recent innovative advances in the study of protein structure/function relationships.

Dr. Matthew J. Gage
Guest Editor

Manuscript Submission Information

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Keywords

  • protein structure
  • protein function
  • biophysics
  • protein-protein interactions
  • single-molecule studies

Published Papers (1 paper)

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Research

12 pages, 4527 KiB  
Article
Interaction of Glutathione with MMACHC Arginine-Rich Pocket Variants Associated with Cobalamin C Disease: Insights from Molecular Modeling
by Priya Antony, Bincy Baby, Amanat Ali, Ranjit Vijayan and Fatma Al Jasmi
Biomedicines 2023, 11(12), 3217; https://doi.org/10.3390/biomedicines11123217 - 04 Dec 2023
Viewed by 834
Abstract
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA [...] Read more.
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA mutase and cytosolic methionine synthase. Depending on the cofactor attached, MMACHC performs either flavin-dependent reductive decyanation or glutathione (GSH)-dependent dealkylation. The alkyl groups of Cbl have to be removed in the presence of GSH to produce intermediates that can later be converted into active cofactor forms. Pathogenic mutations in the GSH binding site, such as R161Q, R161G, R206P, R206W, and R206Q, have been reported to cause Cbl diseases. The impact of these variations on MMACHC’s structure and how it affects GSH and Cbl binding at the molecular level is poorly understood. To better understand the molecular basis of this interaction, mutant structures involving the MMACHC-MeCbl-GSH complex were generated using in silico site-directed point mutations and explored using molecular dynamics (MD) simulations. The results revealed that mutations in the key arginine residues disrupt GSH binding by breaking the interactions and reducing the free energy of binding of GSH. Specifically, variations at position 206 appeared to produce weaker GSH binding. The lowered binding affinity for GSH in the variant structures could impact metabolic pathways involving Cbl and its trafficking. Full article
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