Conformational searching systematic

The program is able to do systematic or random conformation searches using the Tripos force field. Conformation searches can include up to eight single bonds and two rings. 

Most drug-like molecules adopt a number of conformations through rotations about bonds and/or inversions about atomic centers, giving the molecules a number of different three-dimensional (3D) shapes. To obtain different energy minimized structures using a force field, a conformational search technique must be combined with the local geometry optimization described in the previous section. Many such methods have been formulated, and they can be broadly classified as either systematic or stochastic algorithms. 

Systematic searches exhaustively sample conformational space by sequentially incrementing the torsional angles of aU of the rotatable bonds in a given molecule. This conceptually simple approach is straightforward to implement, but scales exponentially with respect to the number of rotatable bonds. To control the exponential increase in the number of potential conformers obtained, systematic searches are usually combined with tree-based search techniques taken from computer science. Even the best implementations of systematic searches become impractical beyond several rotatable bonds (typically greater than 10). Stochastic searches are based on probabiHstic theories and are better suited to calculations... 

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]. 

Because the 3D-structure of the receptor was not yet known, we wanted to derive a pharmacophore model, to prove this hypothesis. Most of the H2-antagonists have much conformational freedom. Evaluation of available crystal data and a systematic conformational search revealed mainly bent conformations,... 

The systematic conformational search for herbarumin I (40) using the MMX force field as implemented in the PCMODEL program revealed the presence of the minimum energy conformation depicted in Fig. 11 (Tmmx = 9.51 kcal/mol), which is related to the chair-chair-chair conformation found in cyclodecane.In this conformation, the value of... 

The algorithm for the systematic conformation search starts with a minimized molecule. The rotatable bonds are selected along with the rotation increment and all possible conformations are created. At this point the search is terminated or each of the proposed conformations is energy minimized according to predefined parameters. After the database of conformers is finalized, each structure is compared to all the other structures through superimposition. Two... 

There are also hybrid methods which combine features from two or all three of the above. Opinions will freely be offered about which technique is best , but the reality is that different techniques will perform differently depending on the problem at hand. Except for very simple systems with only one or a few degrees of conformational freedom, systematic methods are not practical, and sampling techniques, which do not guarantee location of the lowest-energy structure (because they do not look everywhere), are the only viable alternative. By default, Spartan uses systematic searching for systems with only a few degrees of conformational freedom and Monte-Carlo methods for more complicated systems. 

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]. 

Systematic scanning of the potential energy surface, i.e., generation of starting geometries by systematic variation of internal coordinates followed by structure optimization (see energy surface, conformational search). 

The computational study of the osmium dihydroxylation of aliphatic al-kenes is much more complicated than the case of aromatic alkenes due to the large number of conformations that the former could adopt. To overcome this issue, we considered the system to be composed of two different parts the catalyst and the olefin. For the catalyst, the conformation considered is that from the X-ray structure. As already shown in the study of styrene [95], and in some experimental works [98], the catalyst is a fairly rigid molecule. For the aliphatic alkenes under study, there is a large number of possible conformations in addition, the stability of an olefin conformation is also affected by the interactions between the olefin substituent and the catalyst. Therefore, the catalyst must be included in the conformational search. The conformational analysis was done using a scheme based on the systematic search approach [99]. The strategy consisted of two parts first we developed a method to identify all of the possible conformations afterwards, we screened all of the possible conformations at MM level to select the most stable. Finally, we only carried out the relatively expensive QM/MM calculations on these selected conformations. 

Graphs of query and test molecules can be compared by graph matching (subgraph detection) algorithms or systematic comparison of inter-feature distances. Two molecules are considered similar if their pharmacophores match for at least one predicted conformation. In order to explore conformational space and generate conformational ensembles, multiple compound conformations are typically generated by systematic conformational search (in increments) around rotatable bonds. 

As benchmark in the gas phase, we have studied the structure, energy and dipole moment of various conformers in a number of (3-dipeptides ((33-GLY and (33-ALA) and (3-heptapeptides. Systematic conformational searches were carried out for the dipeptides for the heptapeptides, the conformers of interest include the 14-helix and two different 10/12 mixed helical structures [63], As reference, the structures were fully optimized at the B3LYP/6-31+G level, and energies were evaluated at the... 

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