Different dynamics and pathway of disulfide bonds reduction of two human defensins, a molecular dynamics simulation study

Abstract

Human defensins are a class of antimicrobial peptides that are crucial components of the innate immune system. Both human α defensin type 5 (HD5) and human β defensin type 3 (hBD-3) have 6 cysteine residues which form 3 pairs of disulfide bonds in oxidizing condition. Disulfide bond linking is important to the protein structure stabilization, and the disulfide bond linking and breaking order have been shown to influence protein function. In this project, microsecond long molecular dynamics simulations were performed to study the structure and dynamics of HD5 and hBD-3 wildtype and analogs which have all 3 disulfide bonds released in reducing condition. The structure of hBD-3 was found to be more dynamic and flexible than HD5, based on RMSD, RMSF, and radius of gyration calculations. The disulfide bridge breaking order of HD5 and hBD-3 in reducing condition was predicted by two kinds of methods, which gave consistent results. It was found that the disulfide bonds breaking pathways for HD5 and hBD-3 are very different. The breaking of disulfide bonds can influence the dimer interface by making the dimer structure less stable for both kinds of defensin. In order to understand the difference in dynamics and disulfide bond breaking pathway, hydrophilic and hydrophobic accessible surface areas (ASA), buried surface area between cysteine pairs, entropy of cysteine pairs, and internal energy were calculated. Comparing to the wildtype, hBD-3 analog is more hydrophobic, while HD5 is more hydrophilic. For hBD-3, the disulfide breaking is mainly entropy driven, while other factors such as the solvation effects may take the major role in controlling HD5 disulfide breaking pathway. Proteins 2017; 85:665-681. © 2016 Wiley Periodicals, Inc.

Guardians of the Gut: Enteric Defensins

“…Novel discoveries have been made with regard to the structure, functional diversity, and effect on host microbiota of these peptides (Sugi et al, 2017; Zhang, 2017). Many of these discoveries point to a much greater role for defensins in host health and immunity than previously thought.…”

A Dynamic Overview of Antimicrobial Peptides and Their Complexes

“…One interesting structural feature of HBD1, according to NMR data, is the lack of strong and well-defined interactions between secondary structure elements [ 44 ]. Also, deuterium exchange does not indicate the presence of extensive hydrogen bonding between the β-strands [ 45 ]. Also, common structural feature among defensins is their lack of hydrophobic cores and lack of extensive hydrogen bonding, implying conformation plasticity, an important characteristic for biological functions involving differing targets.…”

“…The structure is stabilized primarily by disulfide bonds, allowing it to tolerate extensive residue substitution without disturbing the final tertiary structure. Molecular dynamics simulations performed by Zhang et al revealed microsecond-long motions in α-defensin 5 and β-defensin 3 [ 45 ]. As also shown by their NMR results, despite the presence of disulfide bonds, these defensins present dynamic properties.…”

Defining the mobility range of a hinge-type connection using molecular dynamics and metadynamics

“…Covalent bonding between identical proteins can fulfill numerous purposes depending on the flexibility of the linker. The unstructured highly flexible linker of a Lys-ε-amide bond in ubiquitylation [1,2] allows for the free rotation of the linked domains, while the highly ordered contact surface in dimeric defensin covalently fixed by three intermolecular disulfide bonds prevents any independent mobility of either domain [3]. In both cases, the structural integrity and the resulting dynamics can exert a decisive influence on the biological functions of the proteins [4,5].…”