multiplexing replica exchange molecular dynamics method  (Molecular Dynamics Inc)

Journal: Communications Biology

Article Title: Molecular reshaping of phage-displayed Interleukin-2 at beta chain receptor interface to obtain potent super-agonists with improved developability profiles

doi: 10.1038/s42003-023-05188-0

Figure Lengend Snippet: Electrostatic potential at wild-type (wt) IL-2/IL-2R beta chain interface is analysed in a-b. The backbones of both molecules are represented as grey cartoons. The surface of residues belonging to the interface at either the beta chain side ( a ) or the IL-2 side ( b ) is coloured according to its electrostatic potential. Colour intensity reflects the density of positive (blue) and negative (red) charges. Panels c and d represent two different views of the original interface. IL-2 and IL-2R beta chain backbone cartoons are shown in cyan and green respectively. Side chains of the residues directly involved in the interaction between them are represented as magenta (IL-2) and orange (beta chain) sticks. Yellow dotted lines indicate polar contacts between them. Residues engaged in these contacts are labelled. The structure of free IL-2, with the side chains of residues randomized in phage libraries shown as sticks and labelled, appears in ( e ). Intra-molecular polar contacts between R81 and D84 are indicated. A model of the reshaped interface between one of the beta super-binders ( 80 FDPEDVVE 87 + I92L) and CD122 is represented in ( f ). The new polar contacts established by the residues E83 and E87 (arising from IL-2 phage selection) with positive residues at the beta chain can be appreciated. The search for aggregation-prone regions (amyloid-forming) by WALTZ method underscored two motifs in helices C and D of hIL-2 and its F92-containing version (indicated by asterisks). The length of the putative aggregation-prone motif within helix C was reduced by 50% upon the introduction of the change I92L ( g ). 3D models of hIL-2 variants with replacements at position 92 (after energy minimization with Moe using the amber force field) were used to perform coarse grained Multiplexed Replica Exchange Molecular Dynamics simulations with the UNRES force field. Heat capacity profiles for each variant were constructed according to these results ( h ).

Article Snippet: On the other hand, an exploration of modelled structures of IL-2 variants with mutations at position 92, using Coarse Grained Multiplexed Replica Exchange Molecular Dynamics simulations with the UNRES method , revealed a structural transition in the temperature range 280–290 K for the molecule containing I92F (Fig. ).

Techniques: Selection, Variant Assay, Construct