The Protein Force Field Plays a Crucial Role in Obtaining Accurate Macromolecular Ensembles of IDPs

TL;DR

This study demonstrates that the combination of the AMBER ff19SB force field and OPC water model accurately predicts the conformational ensembles of intrinsically disordered proteins (IDPs) using SAXS data, advancing simulation methods.

Contribution

The paper introduces a validated generalized simulation approach using AMBER ff19SB and OPC water that accurately models both ordered and disordered protein ensembles, including IDPs.

Findings

AMBER ff19SB-OPC water model predicts IDP conformations accurately.

SWAXS-AMDE improves comparison of simulations with SAXS experiments.

Validated approach enhances modeling of protein disorder.

Abstract

Intrinsically disordered proteins (IDPs) play a significant role in intracellular phenomena and are known to exist in an ensemble of inter-converting conformations in solution. Accurately modeling the conformations of IDPs in solution poses a challenge to traditional force fields that are tuned to predict the properties of folded proteins. There is a need for generalized atomistic force fields that can accurately predict the properties of both folded proteins and IDPs. Improvements to protein force fields for increased accuracy in secondary structure prediction and new water models with increased water-water dispersion interactions have been proposed in search of a generalized simulation method. Validating the proposed improvements against experiments poses challenges such as a lack of suitable systems to test the generalizability and choosing a property of interest to match the simulation results against experiments. In this work, we use small angle X-ray scattering (SAXS) data from peptide-based polyampholytes that mimic IDPs to test the generalizability of the AMBER protein force fields and the OPC water model. The specific improvements due to the AMBER ff19SB protein force field and the OPC water model are isolated and studied. Analysis of SAXS profiles and the conformational distribution of polyampholyte sequences show the AMBER ff19SB-OPC water combination to be a generalized model that predicts both ordered polyampholyte sequences and disordered polyampholyte sequences in good agreement with experiments. We have developed a new scattering model termed SWAXS-AMDE that accounts for the hydration layer density changes in atomic detail and is particularly useful in making one-to-one comparisons of simulated scattering profiles to experiments. SWAXS-AMDE allows for the thermal fluctuations of the solute which is particularly consequential for IDPs.