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. 2023 Feb 15;13(2):363.
doi: 10.3390/biom13020363.

Conformational Analysis of Charged Homo-Polypeptides

Lavi S Bigman  1 , Yaakov Levy  1
Affiliations

Conformational Analysis of Charged Homo-Polypeptides

Lavi S Bigman et al. Biomolecules. .

Abstract

Many proteins have intrinsically disordered regions (IDRs), which are often characterized by a high fraction of charged residues with polyampholytic (i.e., mixed charge) or polyelectrolytic (i.e., uniform charge) characteristics. Polyelectrolytic IDRs include consecutive positively charged Lys or Arg residues (K/R repeats) or consecutive negatively charged Asp or Glu residues (D/E repeats). In previous research, D/E repeats were found to be about five times longer than K/R repeats and to be much more common in eukaryotes. Within these repeats, a preference is often observed for E over D and for K over R. To understand the greater prevalence of D/E over K/R repeats and the higher abundance of E and K, we simulated the conformational ensemble of charged homo-polypeptides (polyK, polyR, polyD, and polyE) using molecular dynamics simulations. The conformational preferences and dynamics of these polyelectrolytic polypeptides change with changes in salt concentration. In particular, polyD and polyE are more sensitive to salt than polyK and polyR, as polyD and polyE tend to adsorb more divalent cations, which leads to their having more compact conformations. We conclude with a discussion of biophysical explanations for the relative abundance of charged amino acids and particularly for the greater abundance of D/E repeats over K/R repeats.

Keywords: D/E repeats; K/R repeats; intrinsically disordered proteins; molecular dynamics simulations; polyelectrolytes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Occurrence of proteins with negatively or positively charged polyelectrolytic intrinsically disordered regions (IDRs) in the human proteome. Protein abundance is shown for proteins with D/E or K/R repeats of various lengths, as represented by LDE/KR (i.e., the number of charged residues in the negatively or positively charged homo-polypeptides). The indicated number of proteins (out of the 20,600 proteins in the human proteome) is a cumulative value for all D/E or K/R repeat lengths up to the value of the corresponding LDE/KR. The shortest repeat length in this analysis is a repeat of 10 residues.
Figure 2
Figure 2
Dimensions of charged homo-polypeptides. (A) Violin plots of the Rg values of polyD, polyE, polyK, and polyR polyelectrolytic polypeptides, each constituting 30 residues, at three NaCl concentrations: 0 M, 0.125 M, and 0.25 M. The simulations at 0 M salt concentration included counterions to neutralize the charges of the homo-polypeptides. A polypeptide with 15 GS repeats was also simulated, as a control. The violin plots are colored according to amino acid identity, as indicated by the key. (B) Mean Rg of each charged homo-polypeptide as a function of NaCl concentration.
Figure 3
Figure 3
Conformational ensemble of charged homo-polypeptides. Projection of the first two principal components (PCs) from principal component analysis (PCA) of polyD (orange) and polyR (cyan) at NaCl concentrations of 0 M (left) and of 0.25 M (right). The projection for polyGS (gray) at the corresponding salt concentration is shown in the background of each panel for reference. Adjacent to each panel, a representative conformation is shown for each polyelectrolyte.
Figure 4
Figure 4
Polymeric properties of charged homo-polypeptides. (A) (Left) Flory exponent, υ, of the five simulated polypeptides at three salt concentrations, extracted from the relation Rg ~ |i-j|υ (see main text for details). Error bars are the standard deviation of υ obtained from five independent simulations for each polypeptide. (Right) Representative example of the extraction of υ from the slope when plotting Rg versus |i-j| on a log–log plot. Data are shown for polyE (red circles) and polyGS (gray circles), and the dashed line is the best linear fit. (B) Relaxation times for Rg at three different salt concentrations. Values of τ were extracted by fitting the auto-correlation function, G(t), of Rg to a single exponential function (example on right panel for polyE and polyGS).
Figure 5
Figure 5
Ion adsorption on charged homo-polypeptides. (A) Mean Rg for each system as a function of the mean number of ions adsorbed on each charged homo-polypeptide. The three data points for each charged homo-polypeptide were obtained using simulations at three different concentrations of NaCl (0 M, 0.125 M, and 0.25 M) and two salt concentrations for MgCl2 (0.125 M and 0.25 M). The highest number of adsorbed ions for each system corresponds to simulations at a salt concentration of 0.25 M, with the lowest number of adsorbed ions being found at a salt concentration of 0 M. Filled and empty circles correspond to NaCl and MgCl2, respectively. (B) Two-dimensional distribution of Rg versus number of adsorbed sodium (blue) or magnesium (orange) ions for polyE when simulated in the presence of 0.125 M NaCl or MgCl2. Ion adsorption is defined based on a cutoff distance of 4 Å of the ions from any peptide atom, and the number of adsorbed ions is quantified by averaging the ions that satisfy the cutoff throughout the analyzed trajectory.
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References

    1. Van Der Lee R., Buljan M., Lang B., Weatheritt R.J., Daughdrill G.W., Dunker A.K., Fuxreiter M., Gough J., Gsponer J., Jones D.T., et al. Classification of Intrinsically Disordered Regions and Proteins. Chem. Rev. 2014;114:6589–6631. doi: 10.1021/cr400525m. - DOI - PMC - PubMed
    1. Uversky V.N. The most important thing is the tail: Multitudinous functionalities of intrinsically disordered protein termini. FEBS Lett. 2013;587:1891–1901. doi: 10.1016/j.febslet.2013.04.042. - DOI - PubMed
    1. Oldfield C.J., Dunker A.K. Intrinsically Disordered Proteins and Intrinsically Disordered Protein Regions. Annu. Rev. Biochem. 2014;83:553–584. doi: 10.1146/annurev-biochem-072711-164947. - DOI - PubMed
    1. Das R.K., Ruff K.M., Pappu R.V. Relating sequence encoded information to form and function of intrinsically disordered proteins. Curr. Opin. Struct. Biol. 2015;32:102–112. doi: 10.1016/j.sbi.2015.03.008. - DOI - PMC - PubMed
    1. Uversky V.N., Gillespie J.R., Fink A.L. Why are "natively unfolded" proteins unstructured under physiologic conditions? Proteins. 2000;41:415–427. doi: 10.1002/1097-0134(20001115)41:3<415::AID-PROT130>3.0.CO;2-7. - DOI - PubMed

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Grants and funding

This work was supported by Israel−United States Binational Science Foundation (2020624), by Israel Science Foundation (2072/22), and by a research grant from Estate of Betty Weneser.

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