computer modeling in molecular biology.pdf

238 Oliver S. Smartmoving conformations and intermediates to represent a conformational change, incomparison to the Cartesian application where small atomic deviations producelarge increases in bond energy. Secondly, the use of dihedral angle space allows thedescription of the conformation of a molecule with approximately one-eighth thenumber of independent variables. Finally, the use of dihedral space would enablemore reasonable starting conformations to be generated. Different starting conformationscould be modelled by trying alternative possibilities for dihedral angleswhich change markedly between the fixed end points. Such a method has been usedby Ech-Cherif El-Kettani and Durup [42] to generate initial routes, before applyinga variant of the SPW procedure in Cartesian space. For the reasons set out, an applicationof the PEM method in dihedral angle space can be expected to be verymuch more efficient than the present application and should allow simulation of interestingconformational transitions of macromolecules.8.6 SummaryA new method for the generation of reaction coordinates for conformational transitionsin large molecular systems is presented. The path energy mimimization (PEM)technique optimizes the peak energy of a quasi-continuous route through conformationalspace between two given minima: locating the transition state and the optimalvector through this conformation. The method produces a series of conformationswhich effectively define a reaction coordinate for the change. A transition involvinga pucker angle change for the sugar a-D-xylulofuranose is used to test the procedure.The results are compared with those obtained by both adiabatic mapping and theSelf Penalty Walk procedure developed by Elber and co-workers. The method is appliedto recalculate the energy barrier for a conformational rearrangement of thesubstrate in the active site of D-xylose isomerase, where it is shown to outperforman earlier adiabatic mapping study. Potential improvements to the method werediscussed.AcknowledgementsThis work was supported by the UK Science and Engineering Research Councilunder project grant GR/G49494 and the Molecular Recognition and ComputationalScience Initiatives. I thank Julia Goodfellow, Bonnie Wallace and David Blow forencouragement and many discussions. The ~-xylose isomerase coordinates and reactionmechanism are the result of years of hard work by Charles Collyer, Kim Henrickand Jonathon Goldberg.