computer modeling in molecular biology.pdf

5 Modelling Nucleic Acids 129simulations should help enormously our insight and understanding of the interactionsand dynamics of water molecules around nucleic acids.The present intractability of modelling such an overwhelming amount ofmutually coupled interactions led us to favour interactive graphics techniques formodelling large RNA molecules despite the unavoidable heavy reliance on humanjudgments for selecting local conformations leading to global compactness. Withmodelling conceived as a tool, one might as well take advantage of the capability ofthe human mind to think globally and act locally. Energy minimization andrestrained least-squares are local techniques which perform only within a smallradius of convergence. Although a more global technique, distance geometry, wasrecently introduced in RNA modelling [55], it leads to improbable tangled or knottedstructures that the algorithm cannot remove from the set of solutions. Malhotra etal. [56] have proposed an automatic RNA folding procedure in which a nucleotideis represented as a pseudoatom located at the phosphate atom. Such an approachneglects all the finely grained interactions between helices or loops and helices whichgovern and stabilize the three-dimensional folding [57]. A technique based on a constraintsatisfaction algorithm has been put forward [58]. For small systems, this approachcould be useful, although the software and CPU requirements are heavy(10 hours CPU time on a sophisticated workstation for folding a T-loop). Thedrawbacks of building manually RNA models on graphics systems are real: the processis laborious and can be subjective, since it depends on the judgment of themodeller which is itself based on his knowledge of RNA structures. However, up tonow, it is still the most successful method for large RNAs (see for example themodels of 5s rRNA [59, 601 and the model for the core of group I introns [61-631,especially when modelling is viewed as producing three-dimensional hypothesesdestined to be confronted to experimental verifications via directed mutagenesis andchemical or enzymatic probing.References[l] Konnert, J. H., Hendrickson, W. A., Actu Crystullogr. Sect. A 1980, 36, 344-349.[2] Northrup, S. H., Pear, M. R., McCammon, J. A., Karplus, M., Takano, T., Nuture1980,287, 659-660.[3] Levy, R. M., Sheridan, R. P., Keepers, J. W., Dubey, G. S., Swaminathan, S., Karplus,M., Biophys. J 1985, 48, 509-518.[4] Brooks, C. L., Karplus, M., Pettitt, B. M., Adv. Chem. Phys. 1988, LXXZ.[5] Otting, G., Liepinsh, E., Wiithrich, K., Science 1991, 254, 974-980.[6] Frey, M., in: Water and Biological Macromolecules, Westhof, E. (ed.), Macmillan Press,London 1993, pp. 98-147.[7] Case, D. A., Karplus, M., J. Mol. Biol. 1979, 132, 343-368.