computer modeling in molecular biology.pdf

118 E. WesthoJ C. Rubin-Carrez, and I.: Fritsch5.10 MD of DNA Oligomers with ImplicitSolvent TreatmentThe least amount of distortions in double helical DNA fragments, as compared tocrystallographic results, is observed for simulations with a sigmoidal distance-dependentdielectric function. In (A, T)-rich DNA oligomers, the use of this dielectricfunction has shown that the thymine sugars prefer the 04’-endo pucker, while theadenine sugars adopt preferentially the CT-endo pucker [33]. The hydrogen bondsof the Watson-Crick base pairs are also stable during such simulations, while thethree-center hydrogen bonds typical of dA-dT sequences have lifetimes at least20 times smaller than standard Watson-Crick H-bonds [34]. These simulation resultswere recently further supported by the analysis of the crystal structure of a B-DNAdodecamer d(CGCAAATTTGCG) [35].In MD simulations using a linear dependence on the distance (with either the constant4 or l), severe distortions of the DNA fragments can be observed. Besides, ruptureof Watson-Crick base pairs, especially terminal ones, is systematically observed.The lifetimes of the Watson-Crick pairs are therefore unrealistically low (less than50 ps). The disruption of the Watson-Crick hydrogen bonds leads to the stabilisationof three-center hydrogen bonding and, often, to the formation of odd inter-basepairings. With E = r, there is a strong tendency for forming intramolecular H-bondsbetween exocyclic amino groups (of C or G) and anionic phosphate oxygens or carbony1groups, leading inevitably to severe distortion of the DNA fragments. Thistendency is prominent in minimization studies. Such additional H-bonds were alsoobserved after in vacuo minimization studies of the Z (WC)-DNA model proposedby Ansevin and Wang [36]. Such intramolecular H-bonds are most probably artefactualand result from the simultaneous occurrence of two factors. First, there is a toostrong contribution of the electrostatic interaction between the amino groups and theclosest phosphate group. Secondly, the absence of explicit water molecules preventsthe insertion and bridging of water molecules between amino groups and anionicphosphate oxygens, as commonly observed in crystal structures [lo, 37, 381 and inrecent MD simulations [39]. Figure 5-8 shows examples of such intramolecular H-bonds for an A-A self-pair using the sigmoidal dependence function. It is interestingto note that those artefactual H-bonds were not observed when using E = 4r.Figure 5-9 shows a plot of lnr versus 1/T for the mean lifetimes of the threecenterhydrogen bonds compared to the lifetimes of the adenine sugars in theC2‘-endo domain for poly(dA)-poly(dT) simulated with the sigmoidal dielectricfunction. For comparison purposes, the theoretical curves expected on the basis ofabsolute rate theory are given. The temperature dependences for the two types oflifetimes are similar and much weaker than the theoretical one. One would, thus,conclude that the activation energies governing the three-center H-bonds are of