Biology subjects

Oztekin, A.

Publications and source records attributed to Oztekin, A..

3 recordsLinked to original sources

bioRxiv2026

Danuglipron and orforglipron engage GLP-1R through materially different interfaces: an unbiased molecular dynamics study

GLP-1R is among the most heavily pursued targets in metabolic disease, but its natural agonist is a 30-residue peptide that must be injected. Two oral non-peptide agonists have reached late-stage trials. Cryo-EM studies have already shown that danuglipron and CHU-128, a close analogue of orforglipron, occupy the receptor differently, but not how either interface behaves over time. We ran 500 ns of unbiased all-atom molecular dynamics on GLP-1R bound to GLP-1, danuglipron (PF-06882961) and orforglipron (LY3502970), one trajectory each, in a POPC bilayer with the G protein removed. Although CHU-128 has been simulated before, its analogue, orforglipron, has not. Scored against contacts computed from the deposited structures, under a force field that shares no parameters with previous oral agonist studies, we recovered 80%, 86% and 79% above 50% occupancy. Indexing contact by chemical group, rather than by receptor residue, and normalising by molecular size, separates the two oral compounds: orforglipron carries ring systems dedicated almost entirely to one receptor domain, one of them directing 99.7% of its contact to the extracellular domain, whereas every group of danuglipron engages both. Danuglipron is correspondingly the outlier on measures that do not depend on a chosen threshold: only 33% of its contacts exceed 90% occupancy against 72% and 84%, and it is the only system whose occupancies remain unconverged at 100 ns. With single trajectories, these are observations rather than tested claims, but two drugs of the same class and comparable size occupy this receptor in structurally distinct ways.

biophysics↗

bioRxiv2020

Long time-scale study of von Willebrand factor multimers in extensional flow

Extensional flow-induced transitions from a compact to an unfolded conformation are explored for the human glycoprotein von Willebrand factor (vWF). Multimer unfolding is a crucial step in the process of blood clotting and protein size maintenance. Previous studies have shown that flow-induced conformational transitions are initiated by a thermally nucleated polymeric protrusion. Below a certain strain rate, such a transition is a rare event that cannot be studied using standard stochastic dynamic simulation. In the present study, we have employed Weighted Ensemble Brownian dynamic (WEBD) simulations to study rare events of conformation transition in extensional flow. Results are presented for the transition rate of VWF multimer unfolding, with concomitant analysis of the likelihood of pathological unfolding as a function of strain rate. Relative to the typical half-life of vWF proteins in the human body, results here indicate that pathological unfolding would not manifest for strain rate less than 2000 s-1. Statement of SignificancevWF multimers, as they transit through the circulation, are exposed to extensional flow multiple times, and the total exposure time to such intermittent extensional flow can be on the order of minutes to an hour. However, due to the time-scale limitation of Brownian dynamics simulation, all the present studies of vWF multimers are limited to a few seconds in total duration. Here, we have applied an enhanced sampling technique, i.e., Weighted Ensemble, in combination with Brownian dynamics to analyze the behavior of multimers in extensional flow at physiologically relevant time-scales of hours and longer. The findings presented here provide new physical insights into vWF behavior, including how it relates to hematological pathology, while also illustrating the time-scale bridging capability of the WEBD method.

biophysics↗

bioRxiv2018

Internal Tensile Force and A2 Domain Unfolding of von Willebrand Factor Multimers in Shear Flow

Using Brownian molecular dynamics simulations, we examine the internal dynamics and biomechanical response of von Willebrand Factor (vWF) multimers subject to shear flow. The coarse grain multimer description employed here is based on a monomer model in which the A2 domain of vWF is explicitly represented by a non-linear elastic spring whose mechanical response was fit to experimental force/extension data from vWF monomers. This permits examination of the dynamic behavior of hydrodynamic forces acting on A2 domains as a function of shear rate and multimer length, as well as position of an A2 domain along the multimer contour. Force/position data reveal that collapsed multimers exhibit a force distribution with two peaks, one near each end of the chain; unraveled multimers, however, show a single peak in A2 domain force near the center of multimers. Guided further by experimental data, significant excursions of force acting on a domain are associated with an increasing probability for A2 domain unfolding. Our results suggest that the threshold shear rate required to induce A2 domain unfolding is inversely proportional to multimer length. By examining data for the duration and location of significant force excursions, convincing evidence is advanced that unfolding of A2 domains, and therefore scission of vWF multimers by the size-regulating blood enzyme ADAMTS13, happen preferentially near the center of unraveled multimers.

biophysics↗