Structural mechanism of a drug-binding process involving a large conformational change of the protein target

Abstract

Proteins often undergo large conformational changes when binding small molecules, but atomic-level descriptions of such events have been elusive. Here, we report unguided molecular dynamics simulations of Abl kinase binding to the cancer drug imatinib. In the simulations, imatinib first selectively engages Abl kinase in its autoinhibitory conformation. Consistent with inferences drawn from previous experimental studies, imatinib then induces a large conformational change of the protein to reach a bound complex that closely resembles published crystal structures. Moreover, the simulations reveal a surprising local structural instability in the C-terminal lobe of Abl kinase during binding. The unstable region includes a number of residues that, when mutated, confer imatinib resistance by an unknown mechanism. Based on the simulations, NMR spectra, hydrogen-deuterium exchange measurements, and thermostability measurements and estimates, we suggest that these mutations confer imatinib resistance by exacerbating structural instability in the C-terminal lobe, rendering the imatinib-bound state energetically unfavorable.

G-PLIP: Knowledge graph neural network for structure-free protein-ligand bioactivity prediction

“…In docking-based approaches, the generation of poses is often one of the biggest bottlenecks in structural approaches, as it is challenging to generate plausible binding conformations of protein-ligand complexes without any experimental data. Our observations are consistent with recent studies discussing consistent conformational changes during drug-binding process [62], a challenge that current structural models are still striving to address.…”

Predicting Protein–Ligand Binding and Unbinding Kinetics with Biased MD Simulations and Coarse-Graining of Dynamics: Current State and Challenges

“…As binding events occur much more often than unbinding events, a few long-time unbiased simulations of spontaneous ligand binding do exit in the case of several compounds binding to the β 2 -adrenergic receptor . Very recently, spontaneous binding of Imatinib to Abl kinase has been observed in MD simulations with the help of a simplified weighed ensemble approach. Additionally, binding kinetics can be reconstituted from ensembles of short unbiased simulations with the help of Markov state models. − In a similar vein, binding events can be calculated from the flux between bins in SEEKR and adaptive multisplitting, and ligand-accelerated Gaussian MD allows one to observe both binding and unbinding events, as well.…”

“…The first two challenges are directly connected to each other: as both proteins and ligands are anisotropic bodies and contain internal degrees of freedom, the relevant coordinate space x in its simplest form may already contain the three Cartesian dimensions, as depicted in Figure B for the case of the trypsin–benzamidine complex. , Ligands may perform rotations, which may constitute additional crucial coordinates. This situation becomes much more involved as soon as protein internal degrees of freedom become relevant, e.g., in the form of conformational changes such as in the case of the tyrosine kinase inhibitor Imatinib (also known as Gleevec) binding to its target Abl kinase, − or of helix conformation-binding ligands of the N-terminal domain of heat shock protein 90 (Hsp90) . Finding the relevant coordinate space and CVs that best describe binding and unbinding processes corresponds to the finding of reaction coordinates (RCs).…”

Small molecule activates citrullination through targeting PAD2

“…stabilization of PAD2, especially decreasing its stability in the temperature range of 53 to 57°C (figure 2a and electronic supplementary material, S2A), indicating DMC and jervine binding with PAD2 in vivo. Of interest, both compounds decreased the thermal stability of PAD2, indicating an energetically unfavourable conformation was stabilized after small molecule binding [34][35][36][37]. Considering the high homology among PADs family proteins [15], we further evaluated the engagements of candidates with PAD3 and PAD4.…”