Linkage between proton binding and folding in RNA: implications for RNA catalysis

Small ribozymes use their nucleobases to catalyse phosphodiester bond cleavage. The hepatitis delta virus ribozyme employs C75 as a general acid to protonate the 5′-bridging oxygen leaving group, and to accomplish this task efficiently, it shifts its pKa towards neutrality. Simulations and thermodynamic experiments implicate linkage between folding and protonation in nucleobase pKa shifting. Even small oligonucleotides are shown to fold in a highly co-operative manner, although they do so in a context-specific fashion. Linkage between protonation and co-operativity of folding may drive pKa shifting and provide for enhanced function in RNA.