Fig. 8: Contact profiles of the H3K36 and ssK36 peptides bound to SETD2 observed in the MD simulations.

a Contact frequency difference (4.5 Å cut-off) of SETD2 simulations complexed with H3K36 or ssK36. Shown are all contacts which exhibited a change over 35% frequency, excluding neighbouring residues. Blue indicates that a specific contact was more often observed in simulations with H3K36. Black symbolizes a higher contact frequency for ssK36. The contacts of A/R31 with E1674, T/F32 with E1674 and Q1676 and K/R37 with A1700 have already been observed in the crystal structure analysis¹⁹. The contacts of H/N39 with Y1666 and of ssK36-R40 with M1526 and Q1638 have not been described so far. b Contact frequency difference of SETD2 simulations complexed with H3K36 or ssK36 in catalytically competent conformations. The T32F mutation caused a different structure in catalytically competent conformations as T32 of H3K36 interacts with K1673, while ssK36-F32 interacts with I1602. Moreover, V35 of H3K36 was engaged in more contacts with V1695 than V35 of ssK36. K37 of H3K36 formed different contacts with L1609 and D1665 compared to ssK36-R37, which was more involved in contacts with A1699. N39 of ssK36 preferably interacted with the backbone atoms of Y1666. R40 of ssK36 was more involved in contacts with M1526, E1636 and Q1638 compared to R40 of H3K36. Y41 of ssK36 interacted with P1633, E1636 and T1653, whereas Y41 of H3K36 interacted with M1526 and Q 1638. Snapshots of interaction differences are shown in Supplementary Fig. 10. c Differences in TS-like conformations of H3K36 and ssK36. The distance between the peptide backbone atoms and reference point in the middle of SETD2 was measured. The average distance of N-terminal residues A29–F32 and C-terminal residues P38–P43 of ssK36 to the reference point was lower than for H3K36. However, the residues in the middle of H3K36 were closer to the reference point. See also Supplementary Fig. 11.