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In sickle cell anemia, deoxyhemoglobin deforms RBCs by forming fibrils inside that disintegrate on oxygenation. We studied 100 ns long all-atom molecular dynamics (MD) for sickle and normal hemoglobin fibril models to understand this process, complemented by multiple 1 μs MD for a single tetramer of sickle and normal hemoglobin in deoxy and oxy states. We find that the presence of hydrophobic residues without a bulky side chain at β-6 in hemoglobin is the reason for the stability of the fibrils. Moreover, the free energy landscapes from MD of hemoglobin starting in the tensed (T) state capture the putative transition from T to relaxed (R) state, associated with oxygen binding. The three conformational wells in the landscapes are characterized by the quaternary changes where one αβ dimer rotates with respect to the other. The conformational changes from the oxygenation of sickle hemoglobin hinder the …