Fig. 4: Molecular dynamic simulation of DNAJB1 variants, interacting with HTTExon1Q₄₈.

a Atomistic structure of monomeric DNAJB1^wt. Contact maps of DNAJB1^wt and DNAJB1^H244A, representing contacts of the HBM with surrounding amino acids. Positive values indicate increased and negative decreased interactions within DNAJB1^H244A compared to DNAJB1^wt. b Left, conservation logo of the aligned sequences of class A and B JDP containing a HBM reveal highly conserved E173 and E174 (green square). Right, HTTExon1Q₄₈ aggregation analysis upon addition of Hsc70, Apg2, and DNAJB1^wt or DNAJB1^E173A and DNAJB1^E174A. Each graph is a representative result of three independent experiments. A one-way ANOVA analysis of the T_1/2 of HTTExon1Q₄₈ aggregation is depicted on the right. Bars represent the mean value and error bars correspond to the mean SD. ***P ≤ 0.001; ns not significant. c MD snapshots of monomeric DNAJB1^wt or DNAJB1^H244A, DNAJB1^E173A, and DNAJB1^E174A in complex with HTTExon1Q₄₈ (left). DNAJB1^wt, DNAJB1^H244A, and DNAJB1^E174A with cluster 1 and DNAJB1^E173A with cluster 2 of HTTExon1Q₄₈. Only one monomer was visualized for simplicity, but docking and simulations were performed with dimeric DNAJB1. Atomistic structure of the HBM of DNAJB1^wt or variants and P2 of HTTExon1Q₄₈, interacting via hydrogen bonds (dotted lines) or non-bonding interactions (middle). DNAJB1 (gray) with highlighted amino acids with a coloring code according to the atom types: hydrogen (white), carbon (cyan), oxygen (red), nitrogen (blue). The HBM is colored in cyan. The domains of HTTExon1Q₄₈ are indicated by different colors: polyQ (orange), PRD (P1 and P2: red; residues between P1 and P2: black), N17 (green) and highlighted amino acids in CPK style. Contact maps of DNAJB1^wt or variants and HTTExon1Q_48, focus on the HBM and P2 domain (left). Contact maps were constructed by averaging the contacts over the last 400 ns of the MD simulation and additionally averaging over interactions recorded for cluster 1 and 2 of HTTExon1Q₄₈ with DNAJB1. Distances were converted by a rational switching function, defining the contact distance (inflection point) at 1 nm, where a value of 1 represents a close contact and 0 no contact. Residues 173, 174, and 244 are highlighted with a red box.