Intrinsically disordered peptides (IDPs) defy conventional views of the protein/peptide structure-property paradigm, by conferring function in the absence of a well-defined secondary or tertiary structure.1An interesting sub-class of IDPs comprise peptides that can reversibly switch conformation from random-coil to a well-defined structure, in the presence of an external stimulus.2 To understand this behavior, bioinformatics approaches have sought to correlate sequence motifs and individual residues of IDPs to their structural preferences based on environmental influences.3 4
JAK1 is a de novo designed IDP, comprising Ala-rich segments that favour helical structure at lower temperatures5 as well as the incorporation of Gla (gamma carboxy-glutamic acid), a strong chelator to calcium.It has been proposed that the Gla-rich regions, with their highly-charged side chains, make helical structures unfavourable in the absence of calcium ions. Based on circular dichroism spectroscopy (CD) JAK1 presents a random coil structure in Ca2+-free solution but an alpha helical structure when either adsorbed at the aqueous hydroxyapatite (HA) interface, or in the presence of a strong concentration of free Ca2+ ions in solution. A control peptide, cJAK1 (where Gla → Glu), showed no such behavior, and did not bind to HA. Molecular simulation can provide complementary, in-depth molecular-level insights into this reversible switching mechanism.6 Here, we present results of large-scale Replica Exchange with Solute Tempering (REST) molecular dynamics simulations of JAK1 and cJAK1 in buffer solution, as well as in Ca2+ saturated solution.7 Using Ramachandran plots to investigate secondary structure preferences, and residue-residue contact maps to determine key intra-peptide interactions, we provide molecular level insight into how environmental influences can mediate the conformational switching of JAK1 through side chain interactions.