Sampling of conformational space

Metzler W J, Hare D R and Pardi A 1989 Limited sampling of conformational space by the distance geometry algorithm implications for structures generated from NMR data Bioohemistry 2S 7045-52... 

The structure of a polymer, which is actually many structures generated by a sampling of conformation space, can be obtained via a number of techniques. Some of the most widely used techniques are as follows ... 

Useful for efficient sampling of conformational space in systems such as polymers (92) and peptides (93—95). 

Recent single-molecule experimental studies of proteins provide more detailed views of protein motions, and confirm that a wide variety of timescales is involved in, e.g., catalytic action of enzymes [7,14,15,19,33], Of course, molecular dynamics simulations have been used to probe motions in single proteins for many years, and advances in both theory and computational science have made simulations a powerful approach to building theoretical understanding of protein dynamics [1], The recent introduction of accelerated molecular dynamics methods is helpful in this context [11]. Although detailed dynamical information is sacrificed to the enhanced sampling of conformational space in these methods, which have been shown to access conformational fluctuations that are revealed by nuclear magnetic resonance experiments on the millisecond... 

Ideally, this would mean that the process of modeling based on NMR data could become completely automatic and issues such as sampling of conformational space would become less important as structural definition improves. In practice, what will also happen is that data will accumulate so that prior models become less adequate. Thus, for example, one can expect to see more examples where direct NOE refinement makes the isolated spin... 

W. J. Metzler, D. R. Hare, and A. Pardi, Biochemistry, 28,7045, (1989). Limited Sampling of Conformational Space by the Distance Geometry Algorithm Implications for Structures Generated from NMR Data. 

Constrained Search and the related approach of SCAMPI both integrate the conformational analysis closely with the pharmacophore discovery. This has the advantage that the sampling of conformational space can be more focused on key regions. With both Catalyst and DANTE, conformational analysis was explicitly kept separate, in the latter to allow one to take advantage of any innovations in conformational analysis tools. And, indeed, there continues to be a steady flow of new approaches in conformational analysis—pharmacophore discovery is critically dependent on high-quality exhaustive conformational analysis. Based on our experience thus far, we cannot conclude that either approach is superior (integrated vs. external). Furthermore, a consensus has not yet been reached on the optimal manner to perform conformational search as needed by pharmacophore discovery. This will continue to be a fruitful area of research. 

Large biomolecules with thousands of atoms are an attractive target for semiempirical work. Higher-level ab initio and DFT calculations are very costly for such systems even in the case of QM/MM approaches, especially when considering the need for an adequate sampling of conformational space, and the accuracy of semiempirical methods is normally best for organic compounds. Therefore, semiempirical QM/MM studies on large biomolecules have become very popular in recent years. In particular, many... 

Guntert P, Wuthrich K (2001) Sampling of conformation space in torsion angle dynamics calculations. ComputPhys Commun 138(2) 155-169... 

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