The residence time of the bound water in the hydrophobic minor groove of the carbocyclic-nucleoside analogs of Dickerson-Drew dodecamers.

ABSTRACT

The residence time of the bound water molecules in the antisense oligodeoxyribonucleotides containing 7'-alpha-methyl (TMe) carbocyclic thymidines in duplex (I), d5'(1C2G3C4G5A6A7TMc8TMe9C10G11C12G)23', and 6'-alpha-hydroxy (TOH) carbocyclic thymidines in duplex (II), d5'(1C2G3C4G5AOH6AOH7TOH8 TOH9C10G11C12G)2(3), have been investigated using a combination of NOESY and ROESY experiments. Because of the presence of 7'-alpha-methyl groups of TMe in the centre of the minor groove in duplex (I), the residence time of the bound water molecule is shorter than 0.3 ns. The dramatic reduction of the residence time of the water molecule in the minor groove in duplex (I) compared with the natural counterpart has been attributed to the replacement of second shell of hydration and disruption of hydrogen-bonding with 04' in the minor groove by hydrophobic alpha-methyl groups, as originally observed in the X-ray study. This effect could not be attributed to the change of the width of the minor groove because a comparative NMR study of the duplex (I) and its natural counterpart showed that the widths of their minor grooves are more or less unchanged (r.m.s.d change in the core part is <0.63A). For duplex (II) with polar 6'-alpha-hydroxyl groups pointed to the minor groove, the correlation time is much longer than 0.36 ns as a result of the stabilising hydrogen-bonding interaction with N3 or 02 of the neighbouring nucleotides.