We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach is sufficiently accurate to identify compounds with the desired properties but also to exclude nonpromising ones.

One suggested goal has been the reduction of the spatial separation between workplace and residence through patterns of concentrated multiuse developments. This strategy tends to promote jobs^housing balance, which consequently decreases excess commuting (Levinson, 1998;Scott et al, 1997). The degree of jobs^housing balance (or imbalance) is often measured simplistically as a ratio of jobs to workers (Bookout, 1990;Levine, 1998) and excess commuting is expressed as the difference between the observed average trip length and the theoretical minimum average length (Small and Song, 1992;White, 1988). Commuting is bound tightly with urban structure in the sense that excess commuting in the aggregate is caused by multiple factors, including a locational imbalance of jobs and housing. Household activity schedules and time budgets are critically important too, though such constraints are best tackled using microsimulation rather than the tools in this present paper. We are primarily concerned with the broad-scale analysis of the intrinsic amounts of interaction needed to match workers to places of employment, and we choose to disaggregate zonal data by worker type rather than according to the individual

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DNA photolyase has been the topic of extensive studies due to its important role of repairing photodamaged DNA, and its unique feature of using light as an energy source. A crucial step in the repair by DNA photolyase is the forward electron transfer from its cofactor (FADH(-) ) to the damaged DNA, and the detailed mechanism of this process has been controversial. In the present study, we examine the forward electron transfer in DNA photolyase by carrying out high-level ab initio calculations in combination with a quantum mechanical/molecular mechanical (QM/MM) approach, and by measuring fluorescence emission spectra at low temperature. On the basis of these computational and experimental results, we demonstrate that multiple decay pathways exist in DNA photolyase depending on the wavelength at excitation and the subsequent transition. This implies that the forward electron transfer in DNA photolyase occurs not only by superexchange mechanism but also by sequential electron transfer.

It is known that the formation of the photochemical product of thymine-thymine cyclobutane pyrimidine dimer (TT-CPD) formed upon UV excitation in DNA is significantly affected by the nature of the flanking bases, and that the oxidation potential of the flanking base correlates with the quenching of TT-CPD formation. However, the electronic details of this correlation have remained controversial. The quenching of thymine dimer formation exerted by flanking bases was suggested to be driven by both conformational and electronic effects. In the present study, we examine both of these effects using umbrella sampling and a quantum mechanical/molecular mechanical (QM/MM) approach for selected model systems. Our results demonstrate that a charge transfer (CT) state between the flanking base and the adjacent thymine base can provide a decay pathway for the population to escape from dimer formation, which eventually leads to the formation of an exciplex. The QM/MM vertical excitation energies also reveal that the oxidation potential of flanking bases correlates with the energy level of the CT state, thereby determining whether the CT state intersects with the state that can lead to dimer formation. The consistency between these results and experimentally obtained dimer formation rates implies that the quenching of dimer formation is mainly attributed to the decay pathway via the CT state. The present results further underline the importance of the electronic effects in quenching.

A lot has been learned about the physical and chemical transformations that originate from the absorption of light by DNA, and computational chemistry has played a critical role in revealing the mechanisms of how these transformations occur. Nucleic acids consist of chromophores interacting via π stacking and hydrogen bonding. The fate of these systems after they absorb light is determined by the interplay and competition between pathways involving one chromophore or interacting chromophores. This Perspective highlights the role of π stacking in photophysical and photochemical processes in oligonucleotides and reveals the importance of excimers and exciplexes. Special types of excimers/exciplexes, characterized as bonded excimers/exciplexes, are also found to be important.

KasA (β-Ketoacyl ACP synthase I) is involved in the biosynthetic pathway of mycolic acids, an essential component of the cell wall in Mycobacterium tuberculosis. It was shown that KasA is essential for the survival of the pathogen and thus could serve as a new drug target to treat tuberculosis. The active site of KasA was previously characterized by X-ray crystallography. However, questions regarding the protonation state of specific amino acids, the orientation of the histidine groups within the active site, and additional conformers being accessible at ambient temperatures remain open and have to be addressed prior to the design of new inhibitors. We investigated the active site of KasA in the present work by means of structural motifs and relative energies. Molecular dynamics (MD) simulations, free energy perturbation (FEP) computations, and calculations employing the hybrid quantum mechanics/molecular mechanics (QM/MM) method made it possible to determine the protonation status and reveal important details about the catalytic mechanism of KasA. Additionally, we can rationalize the molecular basis for the acyl-transfer activity in the H311A mutant. Our data strongly suggest that inhibitors should be able to inhibit different protonation states because the enzyme can switch easily between a zwitterionic and neutral state.

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