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FELs for the (a) u-state and (b) p-state systems in 2D PC space constructed by PC1 and PC2. PCA was performed using C α atoms in Atom ID . Two clusters "Clst 1" and "Clst 2" are mentioned in the text.
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To investigate the effects of phosphorylation on the function of the human positive cofactor 4 (PC4), an enhanced molecular dynamics (MD) simulation was performed. The simulation system consists of the N-terminal intrinsic disordered region (IDR) of PC4 and a complex that comprises the C-terminal acidic activation domain of a herpes simplex virion...
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... we use the same expression to estimate the intra-ID SK contact ratio between residues i and j of ID SK as When analyzing the contacts, we have noted artifacts in some snapshots. Figure S4 presents an example of such a snapshot schematically, where ID SK contacts both VP16ad and PC4ctd with the crossing of the periodic boundary. The fraction of those artificial snapshots against the all snapshots was 0.324, and we eliminated them from analyses by setting weight ω k to 0 for those snapshots for both the u-state and pstate systems. ...
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... analyze the structural features of ID SK further, we applied another PCA using the C α atoms only in ID SK (i.e., Atom ID ). Figure 4 portrays the resultant FELs for the two systems. This figure shows that each system has a single major basin whereas each involves thermodynamically less important minor basins. ...
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... figure shows that each system has a single major basin whereas each involves thermodynamically less important minor basins. We applied a clustering method (the single linkage clustering method 51 ) to the ensemble of the p-state system and obtained two clusters: major and minor clusters, which are respectively labeled as Clst 1 and Clst 2 in Figure 4b. The fraction of Clst 2 to Clst 1 was 9%. ...
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... conformations of Figure 5a, which are examples selected from the major free-energy basin (Figure 4a) for the u-state system, were featureless without a characteristic structure. In contrast, the conformations from the major free-energy basin (Clst 1 of Figure 4b) of the p-state system had a feature: the phosphoserine residues in the SEAC segment interacted with lysine or arginine residues in the Krich segment (Figures 5b). ...
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... conformations of Figure 5a, which are examples selected from the major free-energy basin (Figure 4a) for the u-state system, were featureless without a characteristic structure. In contrast, the conformations from the major free-energy basin (Clst 1 of Figure 4b) of the p-state system had a feature: the phosphoserine residues in the SEAC segment interacted with lysine or arginine residues in the Krich segment (Figures 5b). Those interactions are the origin of the specific contact pattern indicated by the white dashed rectangle in Figure 3b. ...
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... results of the present study suggest that the simulation can provide useful atomistic detailed information to understand the functional switch of PC4 by phosphorylation in various systems. 23−28 We detected artificial snapshots in which ID SK contacted both VP16ad and the (PC4ctd) 2 homodimer ( Figure S4) crossing the periodic boundary and eliminated those snap- shots. We presume that the effect of the artificial contact on the VP16ad−(PC4ctd) 2 complex structure is negligible because the helicity of VP16ad was maintained during the simulation. ...
Citations
... PCA has been used to visualize the distribution by projecting the points to a low-dimensional space. 54−57 We applied PCA to the ensembles of the snapshots according to our earlier study, 57 the methodological details of which are explained in Supplementary Section 5. Below we briefly present an outline of the PCA done for this study. The variance-covariance matrix is calculated from atom-pair distances between the whole Cα atoms of PLpro (316 Cα atoms) and the heavy atoms (eight atoms) in a core region of the compound ( Figure S5 of SI). ...
To establish a procedure for screening compounds that inhibit ligand–receptor binding, we used a multidimensional virtual- system coupled molecular dynamics (mD-VcMD), which is a generalized ensemble method developed by ourselves recently. In this sampling method, the compound was put at a distant point from the receptor in the initial conformation of simulation. Both the receptor and the compound were fully flexible in explicit solvent during sampling. The mD-VcMD produced a free-energy landscape of the compound–receptor binding, where a probability of existence was assigned to each sampled conformation. We examined four compounds binding to the papain-like protease (PLpro) of SARS-CoV-2. The resultant free-energy landscapes were funnel-like for all compounds. The probability assigned to the free-energy basins showed good correlation with the measured association constants. Furthermore, structural clustering identified binding modes of two types existing in the free-energy basin. The probability assigned to the binding modes showed good correlation with the measured enzyme-inhibitory. These results suggest that this proposed procedure is useful to select a candidate compound (inhibitor) from examined compounds.
... Therefore, the ensemble of snapshots can be regarded a thermally equilibrated ensemble (canonical ensemble) of the snapshots. This method has been applied to various ligand-receptor systems [26][27][28][29][30][31]. We have proposed three variants of mD-VcMD so far [25]: The original, a subzone-based version, and genetic algorithm-guided mD-VcMD simulations. ...
A small and flexible molecule, ribocil A (non-binder) or B (binder), binds to the deep pocket of the aptamer domain of the FMN riboswitch, which is an RNA molecule. This binding was studied by mD-VcMD, which is a generalized-ensemble simulation method. Ribocil A and B are structurally similar because they are optical isomers to each other. In the initial conformation of simulation, the ligands and the aptamer were completely dissociated in explicit solvent. The aptamer–ribocil B binding was stronger than the aptamer–ribocil A binding, which agrees with experiments. The computed free-energy landscape for the aptamer–ribocil B binding was funnel-like, whereas that for the aptamer–ribocil A binding was rugged. When passing through the gate (named “front gate”) of the binding pocket, each ligand interacted with bases of the riboswitch by non-native π-π stackings, and the stackings restrained the ligand’s orientation to be advantageous to reach the binding site smoothly. When the ligands reached the binding site in the pocket, the non-native stackings were replaced by the native stackings. The ligand’s orientation restriction is discussed referring to a selection mechanism reported in an earlier work on a drug–GPCR interaction. The present simulation showed another pathway leading the ligands to the binding site. The gate (“rear gate”) for this pathway was located completely opposite to the front gate on the aptamer’s surface. However, the approach from the rear gate required overcoming a free-energy barrier regarding ligand’s rotation before reaching the binding site.
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... Therefore, the ensemble of snapshots can be regarded a thermally equilibrated ensemble (canonical ensemble) of the snapshots. This method was applied to various ligand-receptor systems (Higo, et al., 2020b;Higo et al., 2021;Hayami et al., 2021;Higo et al., 2019;Higo et al., 2022;Xie et al., 2023). We have proposed three variants of mD-VcMD so far (Higo et al., 2020a): The original, a subzone-based, and genetic algorithm-guided mD-VcMD simulations. ...
... ; https://doi.org/10. 1101/2023 We set the simulation length of each of 63+ runs to 1 × 10 @ steps (1 × 10 @ × 2 fs = 2.0 ns) for both Ribo-A and Ribo-B systems. Consequently, the total length for an iteration was 2.048 µs (=2.0 ns × 1,024). ...
... ; https://doi.org/10. 1101/2023 This normalization is important to compare =,+1 ( , , ) between the Ribo-A and Ribo-B systems. ...
Binding of a small and flexible molecule, ribocil A (non-binder) or B (binder), to the deep pocket of the aptamer domain of the FMN riboswitch was studied by mD-VcMD, which is a generalized-ensemble method based on molecular dynamics (MD) simulation. Ribocil A and B are structurally similar because they are optical isomers mutually. In the initial conformation of simulation, both ligands and the aptamer were completely dissociated in explicit solvent. The resultant free-energy landscape of ribocil B binding to the aptamer was funnel-like, whereas that of ribocil A was rugged, which agrees qualitatively with an experiment. When entering the gate (named ″front gate″) of the pocket, the ligand interacted with the aptamer by native and non-native π-π stackings, and the stackings restrained the molecular orientation of the ligands to be advantageous to reach the binding site smoothly. The simulation showed another pathway, which also led the ligands to the binding site. Its gate (maned ″rear gate″) located completely opposite to the front gate on the aptamer′s surface. However, approach from the rear gate required overcoming a free-energy barrier before reaching the binding site, and the ligands should rotate largely and sharply at the free-energy barrier. This ligand′s orientation property is discussed referring to a ligand orientation selection mechanism exserted by a membrane protein capturing its ligand.
