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. 2020 Aug 26;21(17):6166.
doi: 10.3390/ijms21176166.

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

Joao V de Souza  1 , Francesc Sabanés Zariquiey  1 , Agnieszka K Bronowska  1   2
Affiliations

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

Joao V de Souza et al. Int J Mol Sci. .

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.

Keywords: CAIPi3P; IDPs; intrinsically disordered proteins; molecular dynamics; water models.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(Left panel) Small-angle X-ray scattering (SAXS) intensities, with a focus on the low angle region. (Right panel) Pair distance distribution function for histatin 5 SAXS.
Figure 2
Figure 2
RMSD matrices and their respective clusters obtained by AMBER03ws. (A) CAIPi3P matrix. (B) TIP4P/2005 matrix. Red and blue molecular representations show the ensembles at the beginning and the end of the trajectory, respectively. The polypeptide chain did not collapse during the simulation using CAIPi3P water model (blue cluster in the top panel), in contrast to the clusters obtained from the simulations using TIP4P, which for the part of the trajectory remained collapsed (red cluster in the lower panel).
Figure 3
Figure 3
Histatin 5′s structural energy in the function of its radius of gyration. An increase in the structural energy is required to attain clusters in the experimental range of radius of gyration. Given the uniform distribution of charged residues throughout the sequence of histatin5, the increase in internal potential energy shows that CAIPi3P increases the solvent–solute interactions.
Figure 4
Figure 4
(Left panel) Small-angle X-ray scattering (SAXS) intensities. (Right panel) Pair distance distribution function for R/S peptide SAXS.
Figure 5
Figure 5
RMSD matrices for the R/S peptide and their respective clusters for AMBER03ws. (A) CAIPi3P matrix (B) TIP4P/2005 matrix. R/S repeat is circled and highlighted yellow.
Figure 6
Figure 6
(Left panel) Small-angle X-ray scattering (SAXS) intensities. (Right panel) Pair distance distribution function for At2g23090 SAXS.
Figure 7
Figure 7
Average structures for the At2g23090. Highly flexible regions (high per-residue RMSF) are coloured red, while more rigid regions with lower per-residue RMSF are coloured blue.
Figure 8
Figure 8
At2g23090 structural energy versus radius of gyration. The increase in structural energy gained by using AMBER03ws unfolded the structured region, stretching the average configuration. When using AMBER99SB-ILDN with CAIPi3P, the energy has been kept within the collapsed AMBER99SB-ILDN+TIP3P. The solvent model stabilised the unstructured sequences, and a structured biased force-field stabilised the intramolecular interactions sufficiently.
Figure 9
Figure 9
(Left panel) LaRP6-RRM1 radius of gyration violin plots; the experimental radius of gyration range is shown as dashed lines. (Right panel) Scattering profile for the LaRP6-RRM1 for simulations with different force field-water model combinations.
Figure 10
Figure 10
Left panel: LaRP6-LaM radius of gyration violin plots; the experimental radius of gyration range is shown by dashed lines. Right panel: scattering profile for the LaRP6-LaM for simulations with different force field–water model combinations.
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