Conformational motion

Abstract. Molecular dynamics (MD) simulations of proteins provide descriptions of atomic motions, which allow to relate observable properties of proteins to microscopic processes. Unfortunately, such MD simulations require an enormous amount of computer time and, therefore, are limited to time scales of nanoseconds. We describe first a fast multiple time step structure adapted multipole method (FA-MUSAMM) to speed up the evaluation of the computationally most demanding Coulomb interactions in solvated protein models, secondly an application of this method aiming at a microscopic understanding of single molecule atomic force microscopy experiments, and, thirdly, a new method to predict slow conformational motions at microsecond time scales. 

As an example for an efficient yet quite accurate approximation, in the first part of our contribution we describe a combination of a structure adapted multipole method with a multiple time step scheme (FAMUSAMM — fast multistep structure adapted multipole method) and evaluate its performance. In the second part we present, as a recent application of this method, an MD study of a ligand-receptor unbinding process enforced by single molecule atomic force microscopy. Through comparison of computed unbinding forces with experimental data we evaluate the quality of the simulations. The third part sketches, as a perspective, one way to drastically extend accessible time scales if one restricts oneself to the study of conformational transitions, which arc ubiquitous in proteins and are the elementary steps of many functional conformational motions. 

The previous application — in accord with most MD studies — illustrates the urgent need to further push the limits of MD simulations set by todays computer technology in order to bridge time scale gaps between theory and either experiments or biochemical processes. The latter often involve conformational motions of proteins, which typically occur at the microsecond to millisecond range. Prominent examples for functionally relevant conformatiotial motions... 

MD simulations are valuable tools if one wants to gain detailed insight into fast dynamical processes of proteins and other biological macromolecules at atomic resolution. But since conventional MD simulations are confined to the study of very fast processes, conformational flooding represents a complementary and powerful tool to predict and understand also slow conformational motions. Another obvious application is an enhanced refinement of Xray- or NMR-structures. 

It is generally recognized that the flexibility of a bulk polymer is related to the flexibility of the chains. Chain flexibility is primarily due to torsional motion (changing conformers). Two aspects of chain flexibility are typically examined. One is the barrier involved in determining the lowest-energy conformer from other conformers. The second is the range of conformational motion around the lowest-energy conformation that can be accessed with little or no barrier. There is not yet a clear consensus as to which of these aspects of conformational flexibility is most closely related to bulk flexibility. Researchers are advised to first examine some representative compounds for which the bulk flexibility is known. 

If we are sufficiently below however, the situation will be markedly different. During the deformation the chain conformational motion will be partially suppressed by neighboring chains, and those motions necessary to relax the chain will be blocked. 

The structure of these globular aggregates is characterized by a micellar core formed by the hydrophilic heads of the surfactant molecules and a surrounding hydrophobic layer constituted by their opportunely arranged alkyl chains whereas their dynamics are characterized by conformational motions of heads and alkyl chains, frequent exchange of surfactant monomers between bulk solvent and micelle, and structural collapse of the aggregate leading to its dissolution, and vice versa [2-7]. 

Reactive intermediates in solution and in the gas phase tend to be indiscriminant and ineffective for synthetic applications, which require highly selective processes. As reaction rates are often limited by bimolecular diffusion and conformational motion, it is not surprising that most strategies to control and exploit their reactivity are based on structural modihcations that influence their conformational equilibrium, or by taking advantage of the microenvironment where their formation and reactions take place, including molecular crystals. ... 

For comparison, the calculated linear and 2D spectra using ft = 12.3 cm-1 and 6 = 52°, which correspond to an a-helical structure (see the contour plot Fig. 19) for the isotopomer Ala -Ala-Ala are shown in Figure 21. The observed spectra for Ala -Ala-Ala are strikingly different from the calculated spectra for a molecule in an a-helical conformation. We emphasize here an important point In contrast to the NMR results on oligo(Ala), in which averaging of different backbone conformations might be present because measurements are made on a time scale that is slow compared to that of conformational motions, these vibrational spectroscopy results are detected on a very fast time scale (Hamm et al, 1999 Woutersen and Hamm, 2000, 2001). This rules out conformational averaging. 

Figure 7. Guest molecules egress from hemicarcerands (Host) through conformational motions known as gating. Gate-opening occurs by (a) French door and (b)...

Morphology based on chemical environment can be probed using F NMR spectroscopy because the chemical shifts of F atoms in the side chains are considerably separated from those in the backbone. Conformational dynamics as affected by domain-selective solvent incorporation are reflected in the widths of static F peaks. These conformational motions, in turn, can influence the migration of solvent penetrants. 

Ostermann, A., Waschipky, R., Parak, R G., Nienhaus, G. U. 2000. Ligand binding and conformational motions in myoglobin. Nature 404 205-8. 

Markwick et al.2U have included in the FTP-DFT analysis of 3hJ(N, C ) couplings in proteins, the effects of the conformation motion such effects were introduced using molecular dynamics simulations. 

Wunderlich, B., Moller, M., Grebowicz, J. and Baur, H. Conformational Motion and Disorder in Low and High Molecular Mass Crystals. Vol. 87, pp. 1-121. 

Schematically the arrangement of a macromolecule with side-chain mesogenic groups in the liquid crystalline state is shown in Fig. 13. Flexible spacers give the mesogenic group its mobility. It is of interest to note that in such liquid crystals all positional mobility of the mesogen is based on conformational motion of the flexible spacer and backbone. Restricting this mobility either prohibits ordering, or freezes the order into the glassy state.

Dynamic features of supermolecules correspond on the intermolecular level to the internal conformational motions present in molecules themselves and define molecular recognition processes by their dynamics in addition to their structural aspects. They add a further important facet to the behaviour of these species and may influence their functional features in reactions and transport processes as well as in polymolecular assemblies. 

Lipkind et al. present their calculations of the conformational motion of maltose [84, 85] based on the assumption that only non bonded interactions and a torsion potential around the glycosidic bond are necessary to describe the energy of a glycoside. They conclude that for maltose there are four conformers with

coupling constants are better described by this four state approach than by a single conformation. 

---