Minimalist approaches

Ot-HehcalBundles. The a-helix is the most extensively studied protein stmctural motif. Because a-hehces form internal hydrogen bonds between the C=0 of residue i and the N—H of residue i + 4 (see Fig. 2), the individual helix is stabili2ed and can exist in isolation. Individual heUces can be manipulated as independent stmctural modules designed to associate in some predetermined manner. Often, a minimalist approach to the design of a-hehces has been taken. In this approach the goal is to obtain the desired stmctural motif using the simplest possible constmction. 

DeGrado, W.E, Wasserman, Z.R., Lear, J.D. Protein design, a minimalist approach. Science 243 622-628, 1989. 

Yet more powerful than the minimalist approach, the optimal consensus Cox2 model displays an excellent training RMS of 0.56 pICso units, for example, R = 0.825, and behaves even better with respect to the external validation set (RMS = 0.53 pICso units, Q2 = 0.841). 

The number of subjects per cohort needed for the initial study depends on several factors. If a well established pharmacodynamic measurement is to be used as an endpoint, it should be possible to calculate the number required to demonstrate significant differences from placebo by means of a power calculation based on variances in a previous study using this technique. However, analysis of the study is often limited to descriptive statistics such as mean and standard deviation, or even just recording the number of reports of a particular symptom, so that a formal power calculation is often inappropriate. There must be a balance between the minimum number on which it is reasonable to base decisions about dose escalation and the number of individuals it is reasonable to expose to a NME for the first time. To take the extremes, it is unwise to make decisions about tolerability and pharmacokinetics based on data from one or two subjects, although there are advocates of such a minimalist approach. Conversely, it is not justifiable to administer a single dose level to, say, 50 subjects at this early stage of ED. There is no simple answer to this, but in general the number lies between 6 and 20 subjects. 

Nevertheless, the importance of the parent molecule remains undeniable, and the reason for it forms the second motivation for the minimalist approach It is the traditional way to bring theory and experiment together for mutual comparison. For decades, chemists have been aware of the limitations on theoretical techniques imposed by computational capacity. Everyone dreamed of the day when the properties of any reasonably sized molecule could be calculated to any desired degree of accuracy. In fact, some computational enthusiasts announced about 25 years ago— prematurely, in my opinion—that the day aheady had arrived. Most chemists were skeptical then they continued under the assumption that the most practical comparisons of theory and experiment would involve experiments on the simplest possible test molecules. Thus, those comparisons accepted the limitations that theory still operated under. 

Aronov, A. M. and Bemis, G. W., A minimalist approach to fragment-based ligand design using common rings and linkers application to kinase inhibitors. Proteins, 2004, 57, 36-50. 

Wang H, Post S, Woods A (2008) A minimalist approach to MALDI imaging of glycerophospholipids and sphingolipids in rat brain sections. Int J Mass Spectrom 278 143-149. doi 10. 1016/j.ijms.2008.04.005... 

Metallopeptide models refer to systems that are mostly unstructured in solntion in the absence of metal ions. It is applicable to design of metal-binding sites whose conserved residues appear mostly in a single peptide that is often much shorter than the whole protein. Designing metalloproteins using only the peptide with the consensus sequence, often called a motif, represents the minimalist approach in its purest sense. These motifs typically contain His, Cys, or both residues. In addition, metalloporphyrin-containing peptides have also been made to mimic basic features in heme proteins. 

The asymptote model is particularly useful for illustrating one of the primary potential drawbacks of not accounting for disease progress. Because patients are expected to improve over time, a simple minimalist approach to the comparison of different drug effects would be expected to be dependent on the time of comparative assessment. If the comparison were made at a point in time where recovery has largely occurred, the difference between treatments would probably be undetectable. 

This chapter summarizes recent theoretical research of proteinase mechanisms as well as novel experimental results which correspond to theoretical suggestions or should be relevant to future theoretical studies. Two major approaches are employed to study enzymatic reactions quantum mechanics and molecular mechanics ("force field") methods. The accuracy of quantum mechanical (QM) methods is still much more diverse than that of force-field approaches, but the most accurate QM methods can be applied only to small systems. This imposes a minimalist approach for the construction of enzyme models forQM studies. 

Molecular graphics visualization software performs an elaborate connect-the-dots process to make the wonderful pictures of protein structure we see in textbooks of biomolecular structure, like the structure for insulin (SINS Isaccs and Agarwa, 1978) shown in Figure 5.1. The connections used are, of course, the chemical bonds between all the atoms. In current use, three-dimensional molecular structure database records employ two different minimalist approaches regarding the storage of bond data. 

Provisions for ascertaining the identity, lot number, and release status of materials, such as bar coding and the like, should not be viewed as excessive, but should be well isolated from the direction and execution of process tasks. Indeed, the objective of the minimalist approach is to reduce to the minimum those connectivities that are superfluous to the basic task of a pilot plant simultaneously prepare material and develop the chemical process. 

A reading of the preamble to the rule reinforces the impression that the drafters have been careful to avoid prescription and bureaucracy wherever possible. However, some has inevitably crept in. There is clearly sensitivity on this point, as a minimalist approach is evident. 

It is important to keep in mind that the product and system concepts developed in this phase are primarily for the purpose of addressing viability, acceptability, and validity. Beyond that which is sufficient to serve this purpose, minimal engineering effort should be invested in these concepts. Beyond preserving resources, this minimalist approach avoids, or at least lessens, ego investments in concepts prior to knowing whether or not the concepts will be perceived to be viable, acceptable, and valid. 

Many operating manuals are cocooned in a cloud of soft materials such as introductions, summaries, generic safety instructions, and company mission statements. None of these materials help the operator do his or her work more efficiently or more safely instead they pad the manual with material that gets in the way, thereby increasing the time it takes find the pertinent instructions. In response to this concern, the minimalist approach eliminates these soft materials. An operating manual should tell the operator how to operate the unit—no more, no less. AU other material should be located in other documents. 

Safety may only be discussed when it has to be, for instance, during mandated safety training or when an accident takes place. If safety communications are seen as unimportant, or not given focus, then the employee base will view safety in the same light. This minimalist approach will lead to little... 

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