Biology subjects

Sisk, T. R.

Publications and source records attributed to Sisk, T. R..

4 recordsLinked to original sources

bioRxiv2025

How small molecules stabilize oligomers of a phase-separating disordered protein

Small molecule inhibitors of the intrinsically disordered androgen receptor activation domain have been tested in clinical trials for the treatment of castration-resistant prostate cancer. These compounds have been shown to stabilize oligomeric forms of the androgen receptor activation domain in solution and alter the properties of androgen receptor condensates. The molecular mechanisms by which small molecules modulate these processes have been poorly understood in atomic detail. Here, we use long-timescale all-atom molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy to determine how small molecules stabilize highly dynamic, heterogeneous intermolecular interfaces that mediate oligomerization of the androgen receptor activation domain. The mechanisms determined here explain the relative potencies of androgen receptor activation domain inhibitors and suggest general strategies for designing small molecules that target oligomeric and, potentially, condensed forms of intrinsically disordered proteins.

biophysics↗

bioRxiv2025

Characterizing structural and kinetic ensembles of intrinsically disordered proteins using writhe

The biological functions of intrinsically disordered proteins (IDPs) are governed by the conformational states they adopt in solution and the kinetics of transitions between these states. We apply writhe, a knot-theoretic measure that quantifies the crossings of curves in three-dimensional space, to analyze the conformational ensembles and dynamics of IDPs. We develop multiscale descriptors of protein backbones from writhe to identify slow motions of IDPs and demonstrate that these descriptors provide a superior basis for constructing Markov state models of IDP conformational dynamics compared to traditional distance-based descriptors. Additionally, we leverage the symmetry properties of writhe to design an equivariant neural network architecture to sample conformational ensembles of IDPs with a denoising diffusion probabilistic model. The writhe-based frameworks presented here provide a powerful and versatile approach for understanding how the structural ensembles and conformational dynamics of IDPs influence their biological functions. Significance StatementIntrinsically disordered proteins (IDPs) are essential for many cellular processes and are implicated in numerous diseases. The biological functions of IDPs are dictated by the populations of the diverse conformational states they adopt in solution and the kinetics of the conformational transitions between these states. Computer simulations are a powerful tool for studying IDPs, but analyzing simulated structural ensembles of IDPs to identify functionally important conformational states and motions remains a significant challenge. In this study, we demonstrate that writhe, a geometric descriptor from the field of knot theory that describes the crossing of curves in space, provides a powerful basis for characterizing the structural ensembles and conformational dynamics of IDPs in atomic detail. Our results provide new tools for unraveling the relationships between IDP sequences, their conformational ensembles, and their biological functions.

biophysics↗

bioRxiv2025

Ensemble docking for intrinsically disordered proteins

Intrinsically disordered proteins (IDPs) are implicated in many human diseases and are increasingly being pursued as drug targets. Conventional structure-based drug design methods that rely on well-defined binding sites are however, largely unsuitable for IDPs. Here, we present computationally efficient ensemble docking approaches to predict the relative affinities of small molecules to IDPs and characterize their dynamic, heterogenous binding mechanisms at atomic resolution. We demonstrate that these ensemble docking protocols accurately predict the relative binding affinities of small molecule -synuclein ligands measured by NMR spectroscopy and generate conformational ensembles of ligand binding modes in remarkable agreement with experimentally validated long-timescale molecular dynamics simulations. Our results display the potential of ensemble docking approaches for predicting small molecule binding to IDPs and suggest that these methods may be valuable tools for IDP drug discovery campaigns.

biophysics↗

bioRxiv2024

Towards accurate, force field independent conformational ensembles of intrinsically disordered proteins

Determining accurate atomic resolution conformational ensembles of intrinsically disordered proteins (IDPs) is extremely challenging. Molecular dynamics (MD) simulations provide atomistic conformational ensembles of IDPs, but their accuracy is highly dependent on the quality of physical models, or force fields, used. Here, we demonstrate how to determine accurate atomic resolution conformational ensembles of IDPs by integrating all-atom MD simulations with experimental data from nuclear magnetic resonance (NMR) spectroscopy and small-angle x-ray scattering (SAXS) with a simple, robust and fully automated maximum entropy reweighting procedure. We demonstrate that when this approach is applied with sufficient experimental data, IDP ensembles derived from different MD force fields converge to highly similar conformational distributions. The maximum entropy reweighting procedure presented here facilitates the integration of MD simulations with extensive experimental datasets and enables the calculation of accurate, force-field independent atomic resolution conformational ensembles of IDPs.

biophysics↗