Microscopic Insight into pH-Dependent Conformational Dynamics and Noncanonical Base Pairing in Telomeric i-Motif DNA

Gene regulatory functions of noncanonical i-motif DNA are associated with dynamic i-motif formation in the cellular environment and pH variation. With atomistic simulations, we show the dramatic influence of solvent pH on the conformational dynamics of biologically relevant telomeric i-motif DNA coupled with protonation of cytosine bases in different conformations. We rationalized the pH-dependent dynamics and conformational variability of the i-motif in terms of base pairing and specific loop motions. The human telomeric i-motif is found to acquire various metastable folded conformations at pH values near the pK_a of cytosine with the formation of a noncanonical C:C W:W trans base pair along with the hemiprotonated C:C⁺ pairs in the i-motif core. pH-dependent dynamics and the local solvent structure of i-motif DNA imply that the presence of a cosolvent or molecular crowding can promote i-motif formation in vivo by changing the conformational fluctuations and hydration state of the structure.