computer modeling in molecular biology.pdf

1 Introduction to Computer Simulation: Methods and Applications 51.5 Flexibility and DynamicsMolecular dynamics methods offer the possibility of studying changes in conformationover a period of time ranging from picoseconds to nanoseconds, as well asestimating average properties of a system at equilibrium. For example, one can seechanges in the pucker of the ribose ring in oligonucleotide conformations or the flexibilityof loop regions in proteins. On a longer timescale, some of the most recentapplications are in the related areas of protein unfolding [13- 161 and stability of peptides[49].It is interesting to study the minimum energy path by which changes in conformationcan occur as such a study provides considerable insight into the behaviour oflarge molecules, and can often be carried out much more rapidly than a full simulationof the process. Techniques to find such reaction coordinates for conformationaltransitions form an important advance in methodology which has only recently beenapplied to biological systems [50, 511. One promising method is described in Chapter8 together with an application related to changes in sugar pucker.1.6 ThermodynamicsAs simulation techniques are compatit.: with the principles of statisticr. mechanics,it is possible to estimate enthalpies and some free energies from simulations ofmolecular systems. As thermodynamic data are usually easier to obtain than structuralinformation for macromolecules in solution, comparison of calculated and experimentalthermodynamic quantities is an important process which gives some indicationof the reliability of a particular simulation. Developments in the 1980s ledto practical ways of estimating differences in free energy between similar systemsusing thermodynamic cycles. As well as providing information which can helpvalidate simulation, such methods are of interest in rational drug design and thedesign of novel molecules. The use of free energy methods allows one to estimatethe difference in equilibrium behaviour of similar proteins (e. g. the stability of wildtype versus mutant proteins) as in Chapter 4, and also to compare the binding of differentligands to the same receptor. Other examples of the application of free energycalculations to understanding biological processes include the study of the transportof ions and solvent through membrane channels, such as that of the simple membranespanning polypeptide gramicidin considered in Chapter 6.