Biology subjects

Duvenci, Z. S.

Publications and source records attributed to Duvenci, Z. S..

3 recordsLinked to original sources

bioRxiv2025

Aggregation-Prone Region Mapping in Olfactomedin Domain of Myocilin through Classical and Enhanced Sampling Molecular Dynamics Simulations

The aggregation of the myocilin olfactomedin (OLF) domain, generally driven by genetic mutations, is the leading cause of primary open-angle glaucoma (POAG). Developing therapeutic strategies requires a detailed understanding its initial unfolding events that expose aggregation-prone regions (APRs). However, it has been a challenge, as the slow conformational dynamics of OLF hinders classical molecular dynamics (MD) simulations from capturing aggregation-prone OLF intermediates. To overcome this, we employed a multi-pronged computational strategy, integrating over 15 {micro}s of simulation time across diverse conditions, including high-temperature, enhanced sampling, chemical denaturation, and simulations of the pathogenic I499F mutant. Our results reveal that OLF unfolding is not random but initiates at specific structural regions pertinent to the terminal blade A and E. Specifically, the blade interfaces between A-B and A-E showed unique regions rich in aromatic/hydrophobic residues as aggregation hotspots. Overall, our simulations proved effective to generate a detailed map of seven distinct APRs. The accuracy of these APRs is partially validated by the close localization of these predicted regions with both previously identified amyloid peptides and the sites of known disease-causing mutations. By scrutinizing the OLF structure and dynamics under different MD settings, our study provides potential molecular targets for developing new therapeutic interventions against POAG.

bioinformatics↗

bioRxiv2024

Computational Modeling of the Anti-Inflammatory Complexes of IL37

Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, particularly through interfering with the IL18 signaling, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. Although the structural homology between IL37 and IL18 suggests a common binding mechanism with the primary members of IL18 signaling, the structures of IL37 complexes have not been experimentally resolvet yet. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations, revealing the structural underpinnings of its modulatory effects on the IL18 signaling pathway. All IL37 protein-protein complexes, including both receptordependent and receptor-independent pairs, were modeled using a range of methods from homology modeling to AlphaFold2 multimer predictions. The models that successfully captured experimental features were subjected to molecular dynamics simulations. As positive controls, binary and ternary PDB complexes of IL18 were also included. The comparative look on the IL37 and IL18 complexes revealed a highly dynamic nature for the IL37 complexes. Repeated simulations of IL37-IL18R showed altered receptor conformations capable of accommodating IL37 in its dimeric form without clashes, providing a structural basis for the failure of IL18R{beta} to be recruited to the IL37-IL18R complex. Simulations of receptor complexes involving various mature forms of IL37 revealed that the N-terminal loop of IL37 is pivotal in modulating receptor dynamics. Additionally, the glycosyl chains on the primary receptor residue N297 act as a steric block against the IL37s N-terminal loop. The interactions between IL37 and IL18BP were also investigated, and our dynamical models indicated that a homologous binding mode was unlikely, suggesting an alternative mechanism by which IL37 functions as an anti-inflammatory cytokine upon binding to IL18BP. Altogether this study accesses to the structure and dynamics of IL37 complexes, offering molecular insights into IL37s inhibitory function within the IL18 signaling pathway and informing future experimental research. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/613817v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@ab5419org.highwire.dtl.DTLVardef@1e7126org.highwire.dtl.DTLVardef@968436org.highwire.dtl.DTLVardef@1c1fec2_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

immunology↗

bioRxiv2024

Rational Design of Monomeric IL37 Variants Guided by Stability and Dynamical Analyses of IL37 Dimers

IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response triggered by IL18 through binding to the IL18 receptor , a capability lost in its dimeric form. This paradigm underscores the pivotal role of IL37s dimer structure in the design of novel anti-inflammatory therapeutics. Hitherto, two IL37 dimer structures were deposited in PDB, reflecting the potential use of their binding interface in the design of IL37 variants with altered dimerization tendencies. Inspection of these static structures suggested a substantial difference in their dimer interfaces. Prompted by this discrepancy, we analyzed the PDB structures of IL37 dimer (PDB: 6ncu and 5hn1) along with a predicted structure by AF2-multimer by molecular dynamics (MD) simulations to unravel whether and how IL37 can form homodimers through distinct interfaces. Results showed that the 5hn1 and AF2 dimers, which shared the same interface, stably maintained their initial conformations throughout the simulations whilst the recent IL37 dimer (PDB ID: 6ncu) with a different interface, did not. These findings underscored that the recent IL37 dimer (6ncu) structure is likely to contain an error, probably in its biological assembly record, otherwise it was not a stable assembly in silico. Next, focusing on the stable dimer structure of 5hn1, we have identified five critical positions of V71/Y85/I86/E89/S114 that would altogether reduce dimer stability without affecting the monomer fold. Two quintet mutations were tested similarly by MD simulations and both mutations showed either partial or complete dissociation of the dimeric form. Overall, this work contributes to the development of IL37-based therapeutics by accurately representing the dimer interface in the PDB structures and identifying five potential substitutions to effectively inhibit the inflammatory response triggered by IL18.

immunology↗