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Conspectus: Bioorthogonal chemistry has had a major impact on the study of biological processes in vivo. Biomolecules of interest can be tracked by using probes and reporters that do not react with cellular components and do not interfere with metabolic processes in living cells. Much time and effort has been devoted to the screening of potential bioorthogonal reagents experimentally. This Account describes how our groups have performed computational screening of reactivity and mutual orthogonality. Our collaborations with experimentalists have led to the development of new and useful reactions. Dozens of bioorthogonal cycloadditions have been reported in the literature in the past few years, but as interest in tracking multiple targets arises, our computational screening has gained importance for the discovery of new mutually orthogonal bioorthogonal cycloaddition pairs. The reactivities of strained alkenes and alkynes with common 1,3-dipoles such as azides, along with mesoionic sydnones and other novel 1,3-dipoles, have been explored. Studies of "inverse-electron-demand" dienes such as triazines and tetrazines that have been used in bioorthogonal Diels-Alder cycloadditions are described. The color graphics we have developed give a snapshot of whether reactions are fast enough for cellular applications (green), adequately reactive for labeling (yellow), or only useful for synthesis or do not occur at all (red). The colors of each box give an instant view of rates, while bar graphs provide an analysis of the factors that control reactivity. This analysis uses the distortion/interaction or activation strain model of cycloaddition reactivity developed independently by our group and that of F. Matthias Bickelhaupt in The Netherlands. The model analyzes activation barriers in terms of the energy required to distort the reactants to the transition state geometry. This energy, called the distortion energy or activation strain, constitutes the major component of the activation energy. The strong bonding interaction between the termini of the two reactants, which we call the interaction energy, overcomes the distortion energy and leads to the new bonds in the products. This Account describes how we have analyzed and predicted bioorthogonal cycloaddition reactivity using the distortion/interaction model and how our experimental collaborators have employed these insights to create new bioorthogonal cycloadditions. The graphics we use document and predict which combinations of cycloadditions will be useful in bioorthogonal chemistry and which pairs of reactions are mutually orthogonal. For example, the fast reaction of 5-phenyl-1,2,4-triazine and a thiacycloheptyne will not interfere with the other fast reaction of 3,6-diphenyl-1,2,4,5-tetrazine and a cyclopropene. No cross reactions will occur, as these are very slow reactions. [ABSTRACT FROM AUTHOR]

Computational chemistry and biochemistry began with Isaac Newton's classical mechanics in the 17th century and the establishment of quantum mechanics in the 1920s. Enabled by extraordinary advances in computers, in the last half century, this field has become a robust partner with experiment. The challenges facing computational chemists and biochemists, the Holy Grails of the field, are described. These include the development of a highly accurate density functional, ideally one that has universal chemical accuracy, and accurate polarizable force fields, as well as methods to handle efficiently the massive number of computations that must be performed for molecular dynamics and for the computation of flexible systems such as proteins. We estimate when the breakthroughs that will make computation a powerful engine for chemical discovery and design will be achieved. The Holy Grails of this field involve methods to enable the accurate and efficient prediction of structures and properties of complex biological systems and materials. The principal Holy Grail is a routine computational method for the prediction and design of multicomponent, often heterogeneous, functional systems and devices. [ABSTRACT FROM AUTHOR]