Structural biology models

Eddy S R 1996. Hidden Markov Models. Current Opinion in Structural Biology 6 361-365. 

Mixmre models have come up frequently in Bayesian statistical analysis in molecular and structural biology [16,28] as described below, so a description is useful here. Mixture models can be used when simple forms such as the exponential or Dirichlet function alone do not describe the data well. This is usually the case for a multimodal data distribution (as might be evident from a histogram of the data), when clearly a single Gaussian function will not suffice. A mixture is a sum of simple forms for the likelihood ... 

Kranss, N., et al., 1996. Photosystem I at 4 A resolution represents the first structural model of a joint photosynthedc reaction centre and core antenna system. Nature Structural Biology 3 965-973. 

There appears now to be ample evidence that the variations in carcinogenicity among the nitrosamines are systematically and rationally related to structure and that several Indices of carcinogenic potency can be used as indices of biological response for the generation of quantitative structure-activity models (11-17). 

Our knowledge of biological membrane ultrastructure has increased considerably over the years as a result of rapid advances in instrumentation. Although there is still controversy over the most correct biological membrane model, the concept of membrane structure presented by Davson and Danielli of a lipid bilayer is perhaps the one best accepted [12,13]. The most current version of that basic model, illustrated in Fig. 7, is referred to as the fluid mosaic model of membrane structure. This model is consistent with what we have learned about the existence of specific ion channels and receptors within and along surface membranes. 

Feig M, Karanicolas J, Brooks CL, III (2004) MMTSB tool set Enhanced sampling and multiscale modeling methods for applications in structure biology. J Mol Graph Model 22 377—395. 

Figure 26. The proposed workflow of structural kinetic modeling Rather than constructing a single kinetic model, an ensemble of possible models is evaluated, such that the ensemble is consistent with available biological information and additional constraints of interest. The analysis is based upon a (thermodynamically consistent) metabolic state, characterized by a vector S° and the associated flux v° v(S°). Since based only on the an evaluation of the eigenvalues of the Jacobian matrix are evaluated, the approach is (computationally) applicable to large scale system. Redrawn and adapted from Ref. 296.

Joint efforts on genomics, proteomics, homology modelling, etc. Receptorbased screening structural biology, especially for the 3D structures of the target and lead both... 

Fig. 3.1 Steps involved in drug discovery approach - a typical example. Joint efforts of classical genomics, proteomics, homology modelling, receptor- or structure-based screening approaches, and finally the structural biology efforts to determine the 3D structures of target reeeptor and receptor-ligand complex to get structural insight info their interactions...

These databases are a rich source of information, yet they do not capture an element of interest, namely the biological endpoint there is no searchable field to identify, in a quantitative manner, what is the target-related activity of a particular compound. Such information is important if one considers that (a) not all chemotypes indexed in patent databases are indeed active - some are just patent claims with no factual basis and that (b) not aU chemotypes disclosed as active are equally active, or selective for that matter, on the target of choice. Furthermore, should one decide to pursue a certain interaction hotspot in a given ligand-receptor structure (assuming good structure-activity models are available), it would be very convenient to mine structure-activity databases for similar chemotypes to use as potential bioisosteric replacements. 

ADME models Structural biology Parallel synthesis Medicinal chemistry... 

The first examples of the so-called supramolecular catalysis are based on bioinspired molecular recognition, which is an essential attribute of biochemical systems. Structures such as receptors, antibodies, and enzymes can all recognize a feature that is important for their specific functions, often in the presence of species of quite similar structure. The ability to discriminate depends exclusively on the structural properties of these biological macromolecules. Recent progress in bioor-ganic chemistry has shown that many of these functions can be incorporated into smaller, synthetically more accessible structures as model systems [27]. 

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