Biology subjects

Yilmaz, S. Z.

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

5 recordsLinked to original sources

bioRxiv2025

Mapping the Peptide Interaction Fingerprint of the Behcet's disease associated HLA-B*51

The strongest genetic risk factor for Behcets disease, a relapsing inflammatory disorder marked by recurrent mucocutaneous ulcers and uveitis, is an allele of the class I major histocompatibility complex (MHC-I) molecule, which presents intracellular peptides to CD8+ T cells. The molecular mechanisms linking the peptide preferences of this allele (HLA-B*51:01) to dysregulated immunity remain unclear, limiting efforts to design peptide-based modulators of antigen presentation. Here, we define HLA-B*51:01s peptide selection rules by mapping the "interaction fingerprint" of 36 self-peptides using long-duration all-atom MD simulations. These uncovered a conserved hydrophobic-polar blueprint that is tuned by peptide length. High-speed atomic force microscopy rate in silico pulling experiments suggest a three-tier hierarchy of mechanical resilience: 9-mers resist the highest forces, 8-mers exhibit intermediate resistance, and 10/11-mers rupture most easily. Our comprehensive analysis provides an atomistic framework for understanding the molecular mechanisms underlying HLA-B*51:01 pathobiology and offers quantitative parameters to guide the design of therapeutic peptides or small molecules to modulate antigen presentation in Behcets disease. STATEMENT OF SIGNIFICANCEBehcets disease is strongly linked to HLA-B*51:01, a molecule that displays protein fragments to killer T cells, yet how this allele selects its peptides is poorly understood. Here, we combine all-atom equilibrium molecular dynamics simulations with steered MD pulling simulations that mimic high-speed atomic force microscopy experiments to map how 36 self-peptides of different lengths engage the HLA-B*51:01 groove. We uncover a conserved hydrophobic-polar interaction blueprint and show that 9-mers form the mechanically most resilient complexes, whereas shorter or longer peptides detach more easily under force. This length-tuned interaction "fingerprint" provides an atomistic framework for understanding HLA-B*51:01-driven immune dysregulation and guides the rational design of peptide-based or small-molecule modulators for Behcets disease.

biophysics↗

bioRxiv2025

Small molecule activator of phosphatase PP2A remodels scaffold PR65 structural dynamics to promote holoenzyme assembly

Small molecule activators of protein phosphatase 2A (PP2A), hereafter SMAPs, have attracted substantial interest, for their potential to inhibit cancer cell proliferation by targeting PR65, the scaffold subunit of the PP2A heterotrimer. PR65 is a uniquely flexible and stable molecule composed of 15 tandem HEAT (Huntingtin, Elongation factor 3-PP2A-TOR1) repeats. We characterized the binding sites and interactions of two SMAPs ATUX-8385 and DT-061 with PR65 and evaluated effects on PR65 structural dynamics using docking and molecular dynamics simulations. We initiated SMAP-bound PR65 simulations starting from two binding sites: S1, determined by cryo-electron microscopy for DT-061 bound to PP2A, on the inner helices of the HEAT repeats 2 and 3 (2i and 3i); and S2, predicted by docking of ATUX-8385 onto PR65, on 4i and 5i and outer helices 5o and 6o consistent with footprinting experiments. S2 proved to be a stable site for both SMAPs when initiating the simulations at S2. However, neither DT-061 nor ATUX-8385 demonstrated stable binding to S1. DT-061 rapidly dissociated from S1 to settle instead at a neighboring site S4 overlapping with our previously identified S3 for PR65 in extended form, suggesting that binding to S1 may be a 2-step process: an initial binding to PR65 alone, either to S3/S4 or S2, followed by movement to S3/S4, and then an induced relocation to S1 upon complexation with the regulatory and catalytic subunits. Targeted in silico mutagenesis showed that mutations at S2 and S4 destabilized SMAP binding to the PR65 (subunit). Heterotrimeric PP2A simulations showed that S3 and S4 binding were not persistent upon complexation. Together, these results corroborate our findings. Furthermore, preferentially stabilized a relatively extended PR65 conformation that would accommodate, if not promote, the assembly of the catalytic and regulatory subunits to prompt the activation of the trimeric phosphatase.

biophysics↗

bioRxiv2023

The Mechanism and Energetics of the Dynein Priming Stroke

Dyneins is an AAA+ motor responsible for motility and force generation towards the minus end of microtubules. Dynein motility is powered by nucleotide-dependent transitions of its linker domain, which transitions between straight (post-powerstroke) and bent (pre-powerstroke) conformations. To understand the dynamics and energetics of the linker, we per-formed all-atom molecular dynamics (MD) simulations of human dynein-2 primed for its power stroke. Simulations re-vealed that the linker can adopt either a bent conformation or a semi-bent conformation, separated by a 5.7 kT energy bar-rier. The linker cannot switch back to its straight conformation in the pre-powerstroke state due to a steric clash with the AAA+ ring. Simulations also showed that an isolated linker has a free energy minimum near the semi-bent conformation in the absence of the AAA+ ring, indicating that the linker stores mechanical energy as it bends and releases this energy during the powerstroke.

biophysics↗

bioRxiv2020

Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells upon binding of its spike (S) glycoproteins to ACE2 receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonding between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and unbinds last from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove an effective strategy to inhibit S-ACE2 interactions.

immunology↗

bioRxiv2020

Exploring Conformational Transition of 2019 Novel Coronavirus Spike Glycoprotein Between Its Closed and Open States Using Molecular Dynamics Simulations

Since its first recorded appearance in December 2019, a novel coronavirus (SARS-CoV-2) causing the disease COVID-19 has resulted in more than 2,000,000 infections and 128,000 deaths. Currently there is no proven treatment for COVID-19 and there is an urgent need for the development of vaccines and therapeutics. Coronavirus spike glycoproteins play a critical role in coronavirus entry into the host cells, as they provide host cell recognition and membrane fusion between virus and host cell. Thus, they emerged as popular and promising drug targets. Crystal structures of spike protein in its closed and open states were resolved very recently in March 2020. These structures comprise 77% of the sequence and provide almost the complete protein structure. Based on down and up positions of receptor binding domain (RBD), spike protein can be in a receptor inaccessible closed or receptor accessible open state, respectively. Starting from closed and open state crystal structures, and also 16 intermediate conformations, an extensive set of all-atom molecular dynamics (MD) simulations in the presence of explicit water and ions were performed. Simulations show that in its down position, RBD has significantly lower mobility compared to its up position; probably caused by the 6 interdomain salt bridges of RBD in down position compared to 3 in up position. Free energy landscapes based on MD simulations revealed a semi-open state located between closed and open states. Minimum energy pathway between down and up positions comprised a gradual salt bridge switching mechanism. Furthermore, although significantly lower than open state, ACE2 binding surface of RBD contained a partial solvent accessibility in its closed state.

biophysics↗