Of protein mechanism

Fisher T E, Oberhauser A F, Carrion-Vazquez M, Marszalek P E and Fernandez J M 1999 The study of protein mechanics with the atomic force microscope Trends Biochem. Sci. 24 379-84... 

In the following sections, we will discuss the influence of several reaction parameters such as temperature, degree of stirring, and the presence of gas/liquid surfaces on the deactivation behavior of proteins. Mechanisms of enzyme inactivation and aggregation are still poorly understood so, in the best case, the rate of activity loss can be correlated with system parameters such as surface area, power input, or collision frequency. However, the ability to control the resistance of an enzyme to inactivation due to exposure to elevated temperatures is essential for the understanding of thermophilic behavior and for developing rational approaches to enzyme stabilization. 

FIGURE 102-5. Nonspecific binding of proteins mechanism. The drug combines with the cell membrane, which in turn causes a nonspecific binding of serum protein. This reaction is seen primarily with the cephalosporins, and no cell lysis or toxicity occurs. Reproduced with permission from Petz LD. Drug-induced haemolytic anaemia. Ballieres Clin Haematol 1980 91 455-482.)... 

Because this problem is complex several avenues of attack have been devised in the last fifteen years. A combination of experimental developments (protein engineering, advances in x-ray and nuclear magnetic resonance (NMR), various time-resolved spectroscopies, single molecule manipulation methods) and theoretical approaches (use of statistical mechanics, different computational strategies, use of simple models) [5, 6 and 7] has led to a greater understanding of how polypeptide chains reach the native confonnation. 

The various folding mechanisms expected in foldable sequences may be classified in tenns of the (Sj,. We have already shown that sequences that fold extremely rapidly have very small values of Gj,. Based on our study of several model proteins as well as analysis of real proteins we classify the folding kinetics of proteins in the following [7]. 

Bryngelson J D and Wolynes P G 1987 Spin glasses and the statistical mechanics of protein folding Proc. Natl Acad. Sci. (USA) 84 7524-8... 

Guo Z and Thirumalai D 1995 Kinetics of protein folding nucleation mechanism, time scales and pathways Biopolymers 36 83-103... 

Shakhnovich E I, Abkevich V and Ptitsyn O 1996 Conserved residues and the mechanism of protein folding Nature 379 96-8... 

Averbukh I Sh, Blumenfeld L A, Kovarsky V A and Perelman N F 1986 A model of the mechanism of enzyme action in terms of protein conformational relaxation Blochim. Blophys. Acta. 873 290-6... 

While simulations reach into larger time spans, the inaccuracies of force fields become more apparent on the one hand properties based on free energies, which were never used for parametrization, are computed more accurately and discrepancies show up on the other hand longer simulations, particularly of proteins, show more subtle discrepancies that only appear after nanoseconds. Thus force fields are under constant revision as far as their parameters are concerned, and this process will continue. Unfortunately the form of the potentials is hardly considered and the refinement leads to an increasing number of distinct atom types with a proliferating number of parameters and a severe detoriation of transferability. The increased use of quantum mechanics to derive potentials will not really improve this situation ab initio quantum mechanics is not reliable enough on the level of kT, and on-the-fly use of quantum methods to derive forces, as in the Car-Parrinello method, is not likely to be applicable to very large systems in the foreseeable future. 

A number of issues need to be addressed before this method will become a routine tool applicable to problems as the conformational equilibrium of protein kinase. E.g. the accuracy of the force field, especially the combination of Poisson-Boltzmann forces and molecular mechanics force field, remains to be assessed. The energy surface for the opening of the two kinase domains in Pig. 2 indicates that intramolecular noncovalent energies are overestimated compared to the interaction with solvent. 

In molecular mechanics and molecular dynamics studies of proteins, assig-ment of standard, non-dynamical ionization states of protein titratable groups is a common practice. This assumption seems to be well justified because proton exchange times between protein and solution usually far exceed the time range of the MD simulations. We investigated to what extent the assumed protonation state of a protein influences its molecular dynamics trajectory, and how often our titration algorithm predicted ionization states identical to those imposed on the groups, when applied to a set of structures derived from a molecular dynamics trajectory [34]. As a model we took the bovine... 

Bryngelson J D and P G Wolynes 1987. Spin Glasses and the Statistical Mechanics of Protein Folding. Proceedings of the National Academy of Sciences LISA 84 7524-7528. 

The consistent force field (CFF) was developed to yield consistent accuracy of results for conformations, vibrational spectra, strain energy, and vibrational enthalpy of proteins. There are several variations on this, such as the Ure-Bradley version (UBCFF), a valence version (CVFF), and Lynghy CFF. The quantum mechanically parameterized force field (QMFF) was parameterized from ah initio results. CFF93 is a rescaling of QMFF to reproduce experimental results. These force fields use five to six valence terms, one of which is an electrostatic term, and four to six cross terms. 

The advantage of molecular mechanics is that it allows the modeling of enormous molecules, such as proteins and segments of DNA. This is why it is the primary tool of computational biochemists. It also models intermolecular forces well. 

A number of molecular mechanics force fields have been parameterized for specific organic systems, such as proteins or hydrocarbons. There are also a... 

This text is similar to that of McCammon and Harvey (see below), but also provides a background for force field-based calculations and a more sophisticated discussion. Includes numerous examples of computing the structure, dynamics, and thermodynamics of proteins. The authors provide an interesting chapter on the complementary nature of molecular mechanics calculations and specific experimental techniques. 

Focuses on force field calculations for understanding the dynamic properties of proteins and nucleic acids. Provides a useful introduction to several computational techniques, including molecular mechanics minimization and molecular dynamics. Includes discussions of research involving structural changes and short time scale dynamics of these biomolecules, and the influence of solvent in these processes. 

---