Conformational ensemble

Fred (Openeye Software) conformational ensembles Gaussian or empirical score... 

M J1990. Calculation of Conformational Ensembles from Potentials of Mean Force. An Approach o the Knowledge-Based Prediction of Local Structures in Globular Proteins. Journal of Molecular Siology 213 859-883. 

To extract the conformational properties of the molecule that is being studied, the conformational ensemble that was sampled and optimized must be analyzed. The analysis may focus on global properties, attempting to characterize features such as overall flexibility or to identify common trends in the conformation set. Alternatively, it may be used to identify a smaller subset of characteristic low energy conformations, which may be used to direct future drug development efforts. It should be stressed that the different conformational analysis tools can be applied to any collection of molecular conformations. These... 

MI Sippl. Calculation of conformational ensembles from potentials of mean force. An approach to the knowledge-based prediction of local structures m globular proteins. I Mol Biol 213 859-883, 1990. 

DM Lorber, BK Shoichet. Flexible ligand docking using conformational ensembles. Protein Sci 7 938-950, 1998. 

The consecuhve levels of 3D informahon are illustrated in Fig. 7.2. The pure cormechvity informahon is usually referred to as 2D. If stereo information is available, it can be referred to as 2.5D since the stereo descriptors add some 3D informahon. From this, a single 3D structure is obtained from the program GORINA [5] and, subsequently, a mulh-conformer ensemble from the program OMEGA [6] (bottom left). In this chapter, we will refer only to the step from 2D (2.5D) to 3D. 

Because of the intrinsic flexibility and poor resonance dispersion of unfolded and partly folded proteins, long-range NOEs are generally very difficult to observe and assign. While observation of a long-range NOE between two protons provides a definitive indication that they are in close proximity in at least some structures in the conformational ensemble, determination of the nature of the folded structures is difficult unless an extensive network of NOEs can be observed. This has so far been achieved in only one case (Mok et al., 1999). 

The calculated cross-sectional area of a molecule (Aocaic) based on the internal amphiphilic gradient of a molecule has been used as the basis for a novel BBB model [40]. For each molecule, a conformational ensemble was generated and the smallest ADca c was chosen. A simple bi-plot of log D7A vs. ADcaic was sufficient to correctly predict the BBB penetration of 85.2% of 122 drugs. 

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