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. 2022 Mar 8;18(3):1915-1928.
doi: 10.1021/acs.jctc.1c00889. Epub 2022 Feb 17.

Modeling the Structure and Interactions of Intrinsically Disordered Peptides with Multiple Replica, Metadynamics-Based Sampling Methods and Force-Field Combinations

Lunna Li  1 , Tommaso Casalini  2 , Paolo Arosio  2 , Matteo Salvalaglio  1
Affiliations

Modeling the Structure and Interactions of Intrinsically Disordered Peptides with Multiple Replica, Metadynamics-Based Sampling Methods and Force-Field Combinations

Lunna Li et al. J Chem Theory Comput. .

Abstract

Intrinsically disordered proteins play a key role in many biological processes, including the formation of biomolecular condensates within cells. A detailed characterization of their configurational ensemble and structure-function paradigm is crucial for understanding their biological activity and for exploiting them as building blocks in material sciences. In this work, we incorporate bias-exchange metadynamics and parallel-tempering well-tempered metadynamics with CHARMM36m and CHARMM22* to explore the structural and thermodynamic characteristics of a short archetypal disordered sequence derived from a DEAD-box protein. The conformational landscapes emerging from our simulations are largely congruent across methods and force fields. Nevertheless, differences in fine details emerge from varying combinations of force-fields and sampling methods. For this protein, our analysis identifies features that help to explain the low propensity of this sequence to undergo self-association in vitro, which are common to all force-field/sampling method combinations. Overall, our work demonstrates the importance of using multiple force-field and sampling method combinations for accurate structural and thermodynamic information in the study of disordered proteins.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
1D-FE profiles of DHH1N for CHARMM36m PTMetaD-WTE, CHARMM22* PTMetaD-WTE, and CHARMM22* unbiased simulations. Error bars are calculated from the Tiwary reweighting scheme, and block averages.−
Figure 2
Figure 2
. 2D-FESs of DHH1N with PTMetaD-WTE on α-content and Rg for CHARMM36m (a) and CHARMM22* (b) with the black dashed lines indicating cluster 1 (α-content ≤ 5), cluster 2 (5 < α-content ≤ 8), and cluster 3 (α-content > 8). Conformations above 20 kJ/mol are not shown in the figure. Purple, red, and yellow parts of the protein highlight the dynamic helical regions of Asn5-Asp18, Asp18-Asp26, and Thr36-Thr42, respectively. The gray clouds represent the sampled conformational space of each annotated state.
Figure 3
Figure 3
Cα–Cα contact maps and secondary structure analysis of DHH1N for CHARMM36m PTMetaD-WTE (a–c), CHARMM22* PTMetaD-WTE (d–f), and CHARMM22* unbiased (g–i), CHARMM36m BEMD (i–j), and finally CHARMM22* BEMD (m–o). The insets of (b, e, h, k, and n) correspond to Rg distributions. The secondary structure assignment is based on the DSSP analysis codes. Error bars are calculated from the Tiwary reweighting scheme, and block averages.−
Figure 4
Figure 4
Comparison between the 1D-FE profiles of DHH1N from PTMetaD-WTE and BEMD simulations. Error bars are calculated from the Tiwary reweighting scheme, and block averages.−
Figure 5
Figure 5
2D-FESs on α-content and Rg for CHARMM36m BEMD (a), CHARMM22* BEMD (b), CHARMM36m PTMetaD-WTE (c), and CHARMM22* PTMetaD-WTE (d). 2D-FESs on α-content and the number of Cα–Cα contact for CHARMM36m BEMD (e), CHARMM22* BEMD (f), CHARMM36m PTMetaD-WTE (g), and CHARMM22* PTMetaD-WTE (h). 2D-FESs on β-content and α-content for CHARMM36m BEMD (i), CHARMM22* BEMD (j), CHARMM36m PTMetaD-WTE (k), and CHARMM22* PTMetaD-WTE (l). The black dashed lines indicate clusters 1 (α-content ≤ 5), 2 (5 < α-content ≤ 5), and 3 (α-content > 8) as defined in Figure 2. The green dashed lines are schematic representation of possible pathways between the α-content minima. The cyan dashed lines indicate the regions primarily occupied by the subgroup of CHARMM36m BEMD with concurring Ala24 and Ser16-Lys22 contacts, which is less explored in all the other simulations.
Figure 6
Figure 6
Cα–Cα contact map and α-helical and β-strand analysis of DHH1N of clusters 1, 2, and 3 for CHARMM36m PTMetaD-WTE (a–d), CHARMM22* PTMetaD-WTE (e–h), CHARMM36m BEMD (i −l), and CHARMM22* BEMD (m–p). The probabilities and propensities are computed relative to the overall population of every cluster. The purple dashed lines highlight possible regions of residues contacts (approximately between Pro28-Thr32 and Pro34-Leu40) that are shared by all simulations.
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