Conformational space searching

Comprehensive conformational space search for protein structure... 

NMR structure determination can be viewed as a global optimization problem for a target function in the conformational space to determine three-dimensional coordinates. The target function is normally a hybrid potential between the NMR-derived structural information and empirical steric conditions. The conformational space means the total degrees of freedom for the atomic positions, typically more than a thousand. The conformational space search for the highly complicated system has been a challenging computational target. 

The distribution properties shown in Fig. 6 strongly depend on protein folding (dependence of hit rates). In practice, a-helix-rich protein has a smoother distribution. This is because of the smaller potential energy barrier of steric repulsion, which results in faster conformational space search (Fig. 5B). The procedure of Fig. 4 can be applied to the proteins with relatively few iterations and short calculation time.66,67... 

As discussed in Section 9, there are approaches to use fewer NOEs for large protein complemented by other more reliable information. The solid-state NMR and solution NMR can be complementary. A large number of poorly precious information can be a trade off with a small number of highly precious information in the high-performance conformational space search (Section 7). 

Goto, H., Kawashima, Y, Kashimura, M., Morimoto, S., and Osawa, E. (1993). Origin of regi-oselectivity in the 0-methylation of erythromycin as elucidated with the aid of computational conformational space search. J. Chem. Soc. Perkin Trans. II1647-1654. 

The dynamic method for selection of active conformers appears to be useful in this venture. Its first step is a procedure for generation of 3D isomers, representing the conformational space of molecules. Although the 3DGEN algorithm is used in the OASIS system, most of the other algorithms for conformational space search (after minor modifications) could be used for that purpose. Next, a method for conformer screening is nsed, based on a hierarchical set ofmles, in an attempt to find the active conformers. 

A conformational space search of medium-sized molecules produces another type of problem how to cope with the thousands of conformers found. They cannot all be checked manually, and some fast way to handle them is needed. Clustering in terms of conformational distance is one of the possible schemes being practiced in this field. For example, the side chain and backbone in Figure 1 should vibrate at different frequencies, and the internal rotations in the side-chain groups may be ignored when dealing with the characteristics of backbone conformation. In such a case, the whole body of conformers found can be classified into clusters differing only in the backbone conformations. 

Conformational space searching has been used to assess the selectivities of O-methylation of erythromycin derivatives. ... 

A similar algorithm has been used to sample the equilibrium distribution [p,(r )] in the conformational optimization of a tetrapeptide[5] and atomic clusters at low temperature.[6] It was found that when g > 1 the search of conformational space was greatly enhanced over standard Metropolis Monte Carlo methods. In this form, the velocity distribution can be thought to be Maxwellian. 

A molecular dynamics simulation samples the phase space of a molecule (defined by the position of the atoms and their velocities) by integrating Newton s equations of motion. Because MD accounts for thermal motion, the molecules simulated may possess enough thermal energy to overcome potential barriers, which makes the technique suitable in principle for conformational analysis of especially large molecules. In the case of small molecules, other techniques such as systematic, random. Genetic Algorithm-based, or Monte Carlo searches may be better suited for effectively sampling conformational space. 

Molecular dynamics simulations are el ficient for searching the conformational space of medium-sized molecules and peptides. Different protocols can increase the elTicieiicy of the search and reduce the computer time needed to sample adequately the available conformations. 

High temperature searches of conformational space (see Quenched Dynamics" on page 78), can produce unwanted conformational changes, such as cis-tmnx peptide flips, ring inversions, and other changes that you cannot reverse easily by geometry optimization. You can use restraints to prevent these changes. 

The choice of bctiling lirnc depends on ibc purpose of llic molecular dynarn ics simulation. If the sim u lalioti is for con form aliori al search es. lb e b catin g step is not critical for a successfti I calculation, The healing step may be rapid lo induce large structural changes that provide access to more of tbc conformational space. 

The book is organised so that some of the techniques discussed in later chapters refer to material discussed earlier, though I have tried to make each chapter as independent of the ofhers as possible. Some readers may therefore be pleased to know that it is not essential to completely digest the chapters on quantum mechanics and molecular mechanics in order to read about methods for searching conformational space Readers with experience in one or more areas may, of course, wish to be more selective. 

Dmparison of various methods for searching conformational space has been performed cycloheptadecane (C17H34) [Saunders et al. 1990]. The methods compared were the ematic search, random search (both Cartesian and torsional), distance geometry and ecular dynamics. The number of unique minimum energy conformations found with 1 method within 3 kcal/mol of the global minimum after 30 days of computer processing e determined (the study was performed in 1990 on what would now be considered a / slow computer). The results are shown in Table 9.1. 

A R 1991, A Survey of Methods for Searching the Conformational Space of Small and Medium-iized Molecules. In Lipkowitz K B and D B Boyd (Editors) Reviews in Computational Chemistry /olume 2. New York, VCH Publishers, pp. 1-55. 

Ferguson D M and D J Raber 1989. A New Approach to Probing Conformational Space with Molecular Mechanics Random Incremental Pulse Search, journal of the American Chemical Society 111 4371-4378. 

Goodman J M and W C Still 1991. An Unbounded Systematic Search of Conformational Space. Journaloj Computational Chemistry 12 1110-1117. 

All of the conformational search methods that were described in Sections 9.2-9.7 have bee used at some stage to explore the conformational space of small pephdes. Here we wi describe some of the methods designed specifically for tackling the problem for peptide and proteins. 

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