Development of Charge-Augmented Three-Point Water Model (CAIPi3P) for Accurate Simulations of Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) are molecules without a fixed tertiary structure, exerting crucial roles in cellular signalling, growth and molecular recognition events. Due to their high plasticity, IDPs are very challenging in experimental and computational structural studies. To provide detailed atomic insight in IDPs’ dynamics governing their functional mechanisms, all-atom molecular dynamics (MD) simulations are widely employed. However, the current generalist force fields and solvent models are unable to generate satisfactory ensembles for IDPs when compared to existing experimental data. In this work, we present a new solvation model, denoted as the Charge-Augmented Three-Point Water Model for Intrinsically Disordered Proteins (CAIPi3P). CAIPi3P has been generated by performing a systematic scan of atomic partial charges assigned to the widely popular molecular scaffold of the three-point TIP3P water model. We found that explicit solvent MD simulations employing CAIPi3P solvation considerably improved the small-angle X-ray scattering (SAXS) scattering profiles for three different IDPs. Not surprisingly, this improvement was further enhanced by using CAIPi3P water in combination with the protein force field parametrized for IDPs. We also demonstrated the applicability of CAIPi3P to molecular systems containing structured as well as intrinsically disordered regions/domains. Our results highlight the crucial importance of solvent effects for generating molecular ensembles of IDPs which reproduce the experimental data available. Hence, we conclude that our newly developed CAIPi3P solvation model is a valuable tool for molecular simulations of intrinsically disordered proteins and assessing their molecular dynamics.

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

“…Efforts aiming to improve all-atom and CG solvation models for IDRs can be categorized into those improving the water model parameters alone or correcting the water/protein/ion interaction potentials. For example, refitting of the point charges in the TIP3P water model was reported to yield more accurately predicted IDP ensembles when validated against SAXS profiles ( de Souza et al, 2020 ). In addition, Gil Pineda et al .…”

Self-Diffusive Properties of the Intrinsically Disordered Protein Histatin 5 and the Impact of Crowding Thereon: A Combined Neutron Spectroscopy and Molecular Dynamics Simulation Study

“…Here, we employ high-resolution neutron backscattering spectroscopy accessing high momentum transfers typically within 0.2 Å –1 < q < 2.0 Å –1 to probe the self-diffusion of the extensively studied, relatively short, IDP, Histatin 5 (Hst5). − We first discuss the experimental results from high-resolution QENS on aqueous solutions of Hst5 in terms of the established models for well-folded proteins with a compact shape. , Hst5 has been well-investigated in terms of structure with SAXS, , NMR, , and circular dichroism, , including investigations on the effect of temperature, crowding, and to limited extent salt, often combined with simulation to further interpret results or benchmark simulation models. − …”

Simulating Polyproline II-Helix-Rich Peptides with the Latest Kirkwood–Buff Force Field: A Direct Comparison with AMBER and CHARMM

“…At first, unbalanced solvation was tackled with an empirical rebalancing of protein–water dispersion interactions − or by parametrizing a new water model with increased water–water dispersion interactions . The importance of protein–water interactions has been specifically investigated within the context of IDP ensembles’ dimension and force field cutoffs .…”