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Mammalian mitochondrial tRNA^Ser(UCN) (mt-tRNA^Ser) and pyrrolysine tRNA (tRNA^Pyl) fold to near-canonical three-dimensional structures despite having noncanonical secondary structures with shortened interhelical loops that disrupt the conserved tRNA tertiary interaction network. How these noncanonical tRNAs compensate for their loss of tertiary interactions remains unclear. Furthermore, in human mt-tRNA^Ser, lengthening the variable loop by the 7472insC mutation reduces mt-tRNA^Ser concentration in vivo through poorly understood mechanisms and is strongly associated with diseases such as deafness and epilepsy. Using simulations of the TOPRNA coarse-grained model, we show that increased topological constraints encoded by the unique secondary structure of wild-type mt-tRNA^Ser decrease the entropic cost of folding by ∼2.5 kcal/mol compared to canonical tRNA, offsetting its loss of tertiary …