Chains errors

By using an effective, distance-dependent dielectric constant, the ability of bulk water to reduce electrostatic interactions can be mimicked without the presence of explicit solvent molecules. One disadvantage of aU vacuum simulations, corrected for shielding effects or not, is the fact that they cannot account for the ability of water molecules to form hydrogen bonds with charged and polar surface residues of a protein. As a result, adjacent polar side chains interact with each other and not with the solvent, thus introducing additional errors. 

Side chain generation is often a source of error. It will be most reliable if certain rules of thumb are obeyed. Start with structurally conserved side chains and hold them fixed. Then look at the energy and entropy of rotamers for the remaining side chains. Conventional conformation search techniques are often used to place each side chain. 

Currently, there is continuing work on an iadustry standard method for the direct determination of monomer, dimer, and trimer acids. Urea adduction (of the methyl esters) has been suggested as a means of determining monomer ia distilled dimer (74). The method is tedious and the nonadductiag branched-chain monomer is recovered with the polymeric fraction. A micro sublimation procedure was developed as an improvement on urea adduction for estimation of the polymer fraction. Incomplete removal of monomer esters or loss of dimer duriag distillation can lead to error (75). 

To put the errors in comparative models into perspective, we list the differences among strucmres of the same protein that have been detennined experimentally (Fig. 9). The 1 A accuracy of main chain atom positions corresponds to X-ray structures defined at a low resolution of about 2.5 A and with an / -factor of about 25% [192], as well as to medium resolution NMR structures determined from 10 interproton distance restraints per residue [193]. Similarly, differences between the highly refined X-ray and NMR structures of the same protein also tend to be about 1 A [193]. Changes in the environment... 

Figure 17.2 An example of prediction of the conformations of three CDR regions of a monoclonal antibody (top row) compared with the unrefined x-ray structure (bottom row). LI and L2 are CDR regions of the light chain, and HI is from the heavy chain. The amino acid sequences of the loop regions were modeled by comparison with the sequences of loop regions selected from a database of known antibody structures. The three-dimensional structure of two of the loop regions, LI and L2, were in good agreement with the preliminary x-ray structure, whereas HI was not. However, during later refinement of the x-ray structure errors were found in the conformations of HI, and in the refined x-ray structure this loop was found to agree with the predicted conformations. In fact, all six loop conformations were correctly predicted in this case. (From C. Chothia et al.. Science 233 755-758, 1986.)...

The amplitudes and the phases of the diffraction data from the protein crystals are used to calculate an electron-density map of the repeating unit of the crystal. This map then has to be interpreted as a polypeptide chain with a particular amino acid sequence. The interpretation of the electron-density map is complicated by several limitations of the data. First of all, the map itself contains errors, mainly due to errors in the phase angles. In addition, the quality of the map depends on the resolution of the diffraction data, which in turn depends on how well-ordered the crystals are. This directly influences the image that can be produced. The resolution is measured in A... 

X-ray structures are determined at different levels of resolution. At low resolution only the shape of the molecule is obtained, whereas at high resolution most atomic positions can be determined to a high degree of accuracy. At medium resolution the fold of the polypeptide chain is usually correctly revealed as well as the approximate positions of the side chains, including those at the active site. The quality of the final three-dimensional model of the protein depends on the resolution of the x-ray data and on the degree of refinement. In a highly refined structure, with an R value less than 0.20 at a resolution around 2.0 A, the estimated errors in atomic positions are around 0.1 A to 0.2 A, provided the amino acid sequence is known. 

The following are some cases (Oil Insurance Association, 1971) in which human error is involved as one of several errors in a chain. 

The time difference (delay) between the measured quantity and the measurement result is called the inertial error. A definition- is the error due to iner tia (mechanical, thermal, etc.) of the parts of a measuring instrument. In ventilation equipment the critical component in the measuring chain, from the dynamic point of view, is often the sensor or the measuring transducer (probe). 

It is therefore useful to distinguish between active and latent errors or failures. An active human error has an immediate effect in that it either directly causes a hazardous state of the system or is the direct initiator of a chain of events which rapidly leads to the imdesirable state. 

Because errors are frequently recoverable, it is also appropriate to define another category of errors, recovery failures. These are failures to recover a chain of events leading to a negative consequence (assuming that such a recovery was feasible) before the consequence occurs. This includes recovery from both active and latent failures. 

The lighter arrows represent typical shortcuts, which omit particular stages in the information-processing chain. These shortcuts may be "legitimate," and would only lead to errors in certain cases. For example, the worker may erroneously believe that he or she recognizes a pattern of indicators and may immediately execute a skill-based response, instead of moving to the rule-based level to apply an explicit diagnostic rule. 

The dotted lines in the diagram indicate the various feedback paths that exist to enable the individual to identify if a particular stage of the processing chain was executed correctly. Thus, if the operating team had planned a strategy to handle a complex plant problem, they would eventually obtain feedback with regard to whether or not the plan was successful. Similar feedback loops exist at the rule and skill-based levels, and indicate opportunities for error correction. The application of the stepladder model to a process industry example is given in Appendix 2A at the end of this chapter. 

FIGURE 2.9. Sequential Model of Error Causation Chain (based on Rasmussen, 1982). 

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