Browsing by Author "Akten, E. Demet"

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pH-Driven β2AR Dynamics Reveal Loop-Mediated Allosteric Communication
(Amer Chemical Soc, 2026) Sogunmez Erdogan, Nuray; Akten, E. Demet
Membrane protein structure and dynamics are highly sensitive to environmental conditions, including changes in pH that can alter the protonation states of ionizable residues and, in turn, influence local electrostatics and stability. Constant-pH molecular dynamics (CpHMD) provides a framework to explore such effects by allowing dynamic proton exchange during simulations. Here, we applied CpHMD at pH:6.5, 7.0, and 8.0, alongside conventional MD, to examine how pH variations may influence the local conformational behaviors of the beta 2-adrenergic receptor (beta 2AR). During the 1.2-mu s-long total simulation, loop regions rich in titratable residues, particularly ICL3 and ECL2, showed the strongest responses to protonation changes. CpHMD trajectories suggested a pH-dependent redistribution of loop flexibility and hydrogen-bonding patterns, producing a see-saw-like effect, while fixed-protonation Control runs showed more constrained behavior. Across all simulations, the key GPCR microswitches, such as the ionic lock, the Y-Y gate, the NPxxY and PIF motifs, and the Trp286-Phe290 toggle pair, stayed within the ranges expected for an inactive receptor. This suggests that pH changes mainly influence local loop motions in the inactive receptor without pushing it toward activation-like states. Finally, mutual information analysis on both C alpha atoms and dihedral angles revealed altered communication between the extracellular and intracellular loops under different pH environments. While limited in time scale, these results provide a computational perspective on how protonation dynamics can modulate the GPCR behavior and highlight the value of incorporating pH effects in molecular-level investigations.
Reshaping Globular Dynamics of S. Aureus Pyruvate Kinase via Bond Restraints to Allosteric Sites
(Springer, 2025) Fidan, Vahap Gazi; Aydin, Dilvin; Yazgi, Irem; Akten, E. Demet
The global dynamics of pyruvate kinase were examined using molecular dynamics (MD) simulations to investigate the effects of allosteric inhibition through bond restraints applied at two key allosteric sites. The study employed the experimentally resolved structure of the enzyme complexed with the allosteric inhibitor IS-130 at the small C-C interface, serving as a reference for analyzing an additional, computationally predicted allosteric site at the large A-A interface. Simulations identified the B and CT domains as the most mobile regions, with bond restraints at either interface significantly reducing CT domain flexibility up to 9 & Aring; across all chains. Restraints at the C-C interface limited minimal global conformational sampling, whereas restraints at the A-A interface altered the dynamic profile without narrowing the sampled conformational space, suggesting distinct regulatory roles for each interface. Distance fluctuation analyses revealed enhanced interchain communication and reduced mobility near restrained sites, suggesting that these restraints reinforce allosteric inhibition by stabilizing otherwise flexible domains. Cross-correlation analysis showed a marked reduction in long-range residue-residue correspondence, especially under C-C restraints, indicating disrupted dynamic coordination essential for catalytic activity. Mutual information analysis, capturing both linear and non-linear dependencies, further supported these findings by showing a widespread loss of dynamic correspondence in positional fluctuations across the receptor upon restraint application. Notably, although the C-C interface has been experimentally linked to inhibition, these results suggest that the computationally predicted large A-A interface may also contribute to allosteric regulation. Together, these findings highlight the distributed and cooperative nature of allosteric control in pyruvate kinase.
Shared Eplets Between Donor Antigens and Patient Antibodies or Mismatched Eplets Between Donor Antigens and Patient Antigens: A Comparison of the Two Algorithms for Predicting Donor-Specific Antibodies
(Wiley, 2025) Karadeniz, Sedat; Hirv, Kaimo; Akten, E. Demet; Oguz, S. Rusdu; Cinar, Cigdem Kekik; Ciftci, Hayriye Senturk; Yelekci, Kemal