computer modeling in molecular biology.pdf

106 E. Westhof; C. Rubin-Carrez, and K Fritschstructures of nucleic acids, i.e. of structures which are not derived from X-raycrystallography. These aspects will be discussed at the end of the article. However,at first, one should calibrate the method and assess the capability of MD techniquesin reproducing structures and dynamical behaviors observed by experimentalmethods.5.3 Water: An Integral Part of Nucleic AcidsNucleic acids are highly charged macromolecules with numerous polar atoms on theheterocyclic bases and on the sugar-phosphate backbone. The tertiary structures ofnucleic acids result therefore from equilibria between (1) electrostatic forces due tothe negatively charged phosphates; (2) stacking interactions between the bases dueto hydrophobic and dispersion forces as well as to hydrogen bonding interactions betweenthe polar atoms of the bases and water molecules; and (3) the conformationalenergy of the sugar-phosphate backbone. In its preferred conformations, thepolynucleotide backbone exposes the negatively charged phosphates to the dielectricscreening by the solvent and promotes the stacked helical arrangement of adjacentbases. In this way, a hydrophobic core is created where hydrogen bond formation betweenthe nucleic acid bases as well as additional sugar-base and sugar-sugar interactionsare favored. Further, via variations in torsion angles of the sugar-phosphatebackbone and through re-orientations of the bases, nucleic acids adapt their structuresso that their polar hydrophilic atoms form favorable interactions with themolecules of the solvent. This interdependence between solvent and nucleic acidstructure constitutes the physicochemical basis for DNA polymorphism. In suchhelical structures, only the internal atoms involved in hydrogen bonding between thebases are protected from solvent while most of the other atoms are accessible towater. Thus, water molecules participate to the overall stability of helical conformationsof nucleic acids by (1) screening the charges of the phosphates; (2) bonding toand bridging between the polar exocyclic atoms of the bases; and (3) influencing theconformations of residues with methyl groups via hydrophobic interactions. Besides,due to the periodicity of the helical structures of nucleic acids, water sites and waterbridges involving polar base atoms or phosphate oxygens lead to structured arrangementsof water molecules, called columns, chains, filaments [12], or spines [13].Extensive reviews have appeared on nucleic acid hydration [lo, 14-16] and we willonly recall some salient points. Similar water binding sites and water bridges arefound repeatedly in small as well as in large nucleic acid crystals. The anionicphosphate oxygen atoms are the most hydrated, the sugar ring oxygen atom 04’ isintermediate, and the esterified 03’ and 05’ backbone atoms are the least hydrated.The hydrophilic atoms of the bases are about equally well hydrated, at half the level