Modeling

Rebuilding the full range of shapes a protein moves through, so rare states and hidden pockets come into view.

A cloud of overlaid protein conformers hovering above a faint free-energy landscape and a subtle compute grid, rendered in violet and cyan on a pale background. Illustrative generated image.
Introduction

A disordered protein is not one structure. It is a probability distribution that must be measured, simulated, and screened as an ensemble.

A single structure suppresses the motion that defines an intrinsically disordered protein. Peptone instead combines target-specific measurements with physics-based simulation to recover a weighted ensemble of interconverting states.

The workflow moves from experimental protection patterns, through enhanced-sampling molecular dynamics and physiological reweighting, to virtual screening against transient, binding-competent conformations.

From measured dynamics to ranked binders

From HDX-MS restraints to a rare, binding-competent state via HOPES enhanced sampling Regional protection measured by hydrogen-deuterium exchange mass spectrometry becomes sparse restraints. HOPES multithermal enhanced sampling explores a broad free-energy landscape in a single replica across many temperatures, reaching low-population states. Reweighting to physiological conditions surfaces a rare, binding-competent folded state, about three percent of the ensemble, consistent with independent NMR and SAXS data. Measured protection HDX-MS in solution HOPES enhanced sampling One replica, many temperatures Rare, relevant states Reweighted to physiology N C Protected regions HDX-MS protection Restraints Conformational coordinate Free energy Broad ensemble Low-population state Barrier Temperature low high Reaches low-population states Reweight Rare folded state A binding-competent pocket opens Population after reweighting Disordered majority ~3% folded Ensemble consistent with NMR + SAXS Ranked binders From HDX-MS restraints to a rare, binding-competent state via HOPES enhanced sampling Regional HDX-MS protection becomes sparse restraints. HOPES multithermal enhanced sampling explores a broad free-energy landscape across many temperatures, reaching low-population states. Reweighting surfaces a rare, binding-competent folded state, about three percent of the ensemble. Measured protection HDX-MS in solution HDX-MS protection Restraints HOPES enhanced sampling One replica, many temperatures Temperature Reaches low-population states Reweight Rare, relevant states Reweighted to physiology Rare folded state A binding-competent pocket opens Population after reweighting Disordered majority ~3% folded Ensemble consistent with NMR + SAXS Ranked binders

HDX-MS protection patterns become sparse restraints that steer HOPES multithermal enhanced sampling across a broad free-energy landscape. Reweighting to physiological conditions surfaces a rare, binding-competent folded state, about three percent of the ensemble, which carries forward to ensemble-aware screening.

Measured dynamics become a screened ensemble Protection measurements feed an ensemble of conformational states, which narrows into screening against a binding-competent pocket.

  1. Measure the accessible landscape

    Automated HDX-MS reads regional protection while the protein remains in solution. Baseline and ligand-induced changes locate dynamic regions and experimentally supported pockets, anchoring the ensemble without forcing the protein into one fixed structure.

  2. Generate and validate the ensemble

    HOPES multithermal sampling lets all-atom simulation escape local traps and visit rare states. Reweighting at physiological conditions yields representative conformers, then independent NMR, SAXS, and mass-spectrometry observables test whether the ensemble agrees with experiment.

  3. Screen states, not snapshots

    Virtual screening runs across population-weighted conformers rather than one structural guess. Candidates advance when their interactions remain consistent across plausible states and stabilize a binding-competent pocket, focusing chemistry on hypotheses supported by both physics and experiment.

Academic collaboration advances rare-state modeling

UCPH

Copenhagen N, Denmark

Prof. Kresten Lindorff-Larsen

Professor of Computational Protein Biophysics, Department of Biology

Revealing rare, transiently structured states in disordered proteins through multithermal simulation and experimental reweighting.

Read the collaboration

Computation that expands with the question

Our modeling workloads expand and contract with each target. Enhanced sampling, ensemble generation, physiological reweighting, and compound evaluation each move through a different computational regime, so the platform provisions only the capacity a given stage needs.

Elastic cloud infrastructure supplies orchestration, storage, and on-demand scale, while GPU-accelerated computing and the BioNeMo framework provide optimised tools for molecular simulation, model training, and inference. Together they let Oppenheimer and PepTron-o move target-specific data through the modeling loop without separating computation from the experimental evidence that governs it.

Accelerated computing at Peptone

A short film on the infrastructure behind Peptone's ensemble-first, experimentally grounded drug-discovery platform.

In collaboration with

At a glance

  • Target-specific HDX-MS evidence integrated with ensemble generation
  • HOPES multithermal sampling reweighted to physiological conditions
  • Oppenheimer and PepTron-o ensemble generation on accelerated infrastructure
  • Ensemble populations tested against independent NMR, SAXS, and mass-spectrometry observables
  • Virtual screening across transient, population-weighted pockets
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