The nucleosome core particle (NCP) is a fundamental unit of genome packaging, wherein
147 base pairs DNA is wrapped ~1.7 times around histone octamer (two copies each of
histone proteins H2A, H2B, H3 and H4). Each histone is equipped with flexible tails that
extend out from the NCP surface; these tails are essential for chromatin signaling. Here we investigate, both experimentally and via MD modeling, the dynamic behavior and structural propensities of the N-terminal tail of histone H4. First, we assigned the observable HSQC NMR resonances (residues 1-15 of H4) in the reconstituted NCP sample and measured the corresponding 15N relaxation rates. The results suggest that N-terminal portion of the tail, termed N-H41-15, is conformationally flexible, although its motion is slowed down by about 10-fold compared to a free peptide with the same sequence. Next, we turn to paramagnetic relaxation enhancement (PRE) measurements to directly probe the positioning of N-H41-15 tails. For this purpose we have prepared four NCP samples nitroxide spin-labeled at different H3 sites. To interpret the experimental results, we rely on microsecond-long MD simulations of nucleosome particle in explicit water. Remarkably, both PRE rates and 15N relaxation rates measured in N-H41-15 tail are in good agreement with the corresponding MD-based calculated data. Collectively, our results suggest that H4 tail is engaged in “fuzzy interaction” with nucleosomal DNA. This work was in part supported by the SPbU grant AAAA-A16-116102010033-6.