Conformational search method

Judson R S, W P Jaeger, A M Treasurywala and M L Peterson 1993. Conformational Searching Methods for Small Molecules. 2. Genetic Algorithm Approach. Journal of Computational Chemistry 14 1407-1414. 

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. 

The generation of loops is necessary because disconnected regions are often separated by a section where a few amino acids have been inserted or omitted. These are often extra loops that can be determined by several methods. One method is to perform a database search to find a similar loop and then use its geometric structure. Often, other conformation search methods are used. Manual structure building may be necessary in order to find a conformation that connects the segments. Visual inspection of the result is recommended in any case. 

To overcome the limitations of the database search methods, conformational search methods were developed [95,96,109]. There are many such methods, exploiting different protein representations, objective function tenns, and optimization or enumeration algorithms. The search algorithms include the minimum perturbation method [97], molecular dynamics simulations [92,110,111], genetic algorithms [112], Monte Carlo and simulated annealing [113,114], multiple copy simultaneous search [115-117], self-consistent field optimization [118], and an enumeration based on the graph theory [119]. 

The most serious problem with MM as a method to predict molecular structure is convergence to a false, rather than the global minimum in the Born-Oppenheimer surface. The mathematical problem is essentially still unsolved, but several conformational searching methods for approaching the global minimum, and based on either systematic or random searches have been developed. These searches work well for small to medium-sized molecules. The most popular of these techniques that simulates excitation to surmount potential barriers, has become known as Molecular Dynamics [112]. 

G-Protein-coupled receptors do not lend themselves to analysis by either NMR or x-ray crystallography due to their structural dependence on an intact cell membrane. In our laboratories we pursued this valuable structural information by utilizing a combination of structural homology modeling, molecular dynamics, systematic conformational searching methods, and mutagenesis experiments. The combination of these techniques led to a proposed model of bradykinin bound to the agonist site on its receptor [41]. 

Conformational Search Method for Docking Flexible Molecules Using Molecular Similarity. 

The combination of free MD simulations with conformational search methods, in particular methods which use the information contained in structural databases, can provide an efficient sampling tool. 

S. Makino and I. D. Kuntz. ELECT++ Faster conformational search method for docking flexible molecules using molecular similarity. Journal of Computational Chemistry, 19 1834-1852, 1998. 

The basic principles of the distance geometry approach have been described in Sec. 3.4. There, it was mentioned that the embedding procedure can produce several molecular geometries that do not violate the preset distance restrictions. Therefore, distance geometry per se can be regarded as a conformational search method. 

Each program was used to generate conformational ensembles for the compounds in the data set. To find out whether the conformational search method under consideration is able to reproduce biologically active conformations within the ensembles of conformations, the computed conformations were compared to their x-ray geometries (receptor-bound conformations) by applying a distance measure in Cartesian space (i.e., the RMS rz deviation of the corresponding atoms). 

The availability of any experimental data, the accessibility of computational resources, and (perhaps most importantly) what the results are to be subsequently used for are all factors to take into account when choosing a search strategy. New experimental techniques, advances in theory, and improved computer hardware have all played important roles in the development of conformational search methods and will undoubtedly play similar roles in the future. The coming years promise many exciting developments in this field. 

Molecular model-building (conformational search) methods fall into two general classes systematic and random. - Systematic methods search all possible combinations of torsional angles, whereas random methods usually involve a Monte Carlo (with Metropolis sampling ) or molecular dynamics trajectory. Both approaches attempt to search large areas of conformational space and eventually converge on the desired conformation or structure. Dis-... 

Another grouping of the various conformation search methods is based on the coordinate system in which they operate. For the potential advantages of the external (Cartesian) and internal (bond lengths, bond and torsional angles) systems, the reader is referred to Refs. 71 and 75. 

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