Nucleosome unwrapping governs chromatin accessibility and gene regulation, yet the molecular determinants of unwrapping directionality remain poorly understood. Using atomistic and SIRAH coarse-grained umbrella sampling simulations, we show that DNA sequence and histone variant composition jointly tune a directional preference for nucleosome unwrapping. For both the ASP and Widom-601 sequences, unwrapping initiates asymmetrically from a preferred DNA end, with progressive disengagement of the H3 N-terminal tail providing the molecular switch that determines directionality in the Widom-601 system. Substitution of canonical H2A with the variant H2A.Z reverses this directional preference, shifting unwrapping to the opposite DNA end and altering the free energy landscape. SIRAH coarse-grained simulations faithfully reproduce these sequence- and variant-dependent unwrapping pathways and their qualitative free energy features, though quantitative barrier heights differ from atomistic values, identifying a target for further force field refinement. Together, these results establish H3 tail - DNA disengagement as a key mechanistic determinant of unwrapping directionality, reveal how a single histone variant substitution can reverse this preference, and validate SIRAH as an efficient framework for large-scale chromatin simulations.
GHOSH MOULICK, A., Patel, R., Rajpersaud, T., Loverde, S.
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