Quantum mechanics computational biochemistry application

The exponential increase in computer power and the development of highly efficient algorithms has distinctly expanded the range of structures that can be treated on a first-principle level. Using parallel computers, AIMD simulations of systems with few hundred atoms can be performed nowadays. This range already starts to approach the one relevant in biochemistry. Indeed, some simulations of entire biomolecules in laboratory-realizable conditions (such as crystals or aqueous solutions) have been performed recently [25-28]. For most applications however, the systems are still too large to be treated fully at the AIMD level. By combining AIMD simulations with a classical MD force field in a mixed quantum mechanical/molecular mechanical fashion (Hybrid-AIMD) the effects of the protein environment can be explicitly taken into account and the system size can be extended. 

The accurate prediction of enzyme kinetics from first principles is one of the central goals of theoretical biochemistry. Currently, there is considerable debate about the applicability of TST to compute rate constants of enzyme-catalyzed reactions. Classical TST is known to be insufficient in some cases, but corrections for dynamical recrossing and quantum mechanical tunneling can be included. Many effects go beyond the framework of TST, as those previously discussed, and the overall importance of these effects for the effective reaction rate is difficult (if not impossible) to determine experimentally. Efforts are presently oriented to compute the quasi-thermodynamic free energy of activation with chemical accuracy (i.e., 1 kcal mol-1), as a way to discern the importance of other effects from the comparison with the effective measured free energy of activation. 

These successes did not go unnoticed by industry. Several pharmaceutical companies (1963-1964) became interested in applications of it-electron theory to biochemistry. While it was admittedly premature, it was felt that quantum chemistry was both the wave of the future and the very matrix for rational drug design. Hiickel energies of cephalosporins could be correlated with their biological activities.While companies were applying some mathematical methods of correlation techniques in quantitative structure-activity relationships (QSAR), it was chiefly the Hiickel theory and various forms of semiempirical quantum mechanics that was using a large share of computer time on the IBM 7094 mainframe in 1966. 

Macromolecules are very diverse in composition and function and they occur in many fields of chemistry and biochemistry. The usual applications of synthetic polymers mainly deal with their physical properties molecular weight, conformations, van des Waals interactions... which don t require detailed knowledge of the electronic structure and can be approached by classical computational force fields which are at the basis of what one usually calls molecular mechanics. Nevertheless, one may be interested in the chemical reactivity of some region of the polymer, such as structural defects, and a quantum computation may be the only way to get the reliable chemical information. The other, very important class of macromolecules contains the innumerable biomacromolecules polypeptides, enzymes, nucleic acids. The understanding of their role in life usually requires the knowledge of the electronic structure and often the reactivity of at least well defined parts of the large system they constitute. This knowledge can only be reached by means of quantum chemical computations. 

Electronic chiroptical phenomena are among the oldest to be noted in chemistry. Understanding of the phenomena required first the introduction of quantum mechanics, and then the advent of computers sufficiently powerful to predict chiroptical properties for real molecules. The availability of excellent commercial instrumentation and pervasive applications in the sphere of biochemistry have maintained the field of ECD research as a mature but healthy one. 

Cobalamins are essential enzymatic cofactors in human biochemistry. Coba-lamins chemical structure is based on the tetrapyrrole ring, while the chemical properties of the Co bond located in the centre of their moiety have been the focus of extensive research. Cyanocobalamin, the most known form of cobalamins, is rarely found in nature. Methylcobalamin and adenosylcobalamin are the two active forms of cobalamins in vivo in humans. Weakening of the Co C bond and its homolytic or heterolytic cleavage have been uncovered as an essential mechanism in the biochemical role of cobalamins as cofactors in humans. Recent studies using modem computational methods and application of quantum chemistry models have widened our knowledge of cobalamins biochemistry and are expected to contribute to our further understanding of cobalamin-dependent enzymes. 

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