Molecular modeling at the atomic level has been applied in a wide range of biological systems. The widely adopted additive force fields typically use fixed atom-centered partial charges to model electrostatic interactions. However, the additive force fields cannot accurately model polarization effects, leading to unrealistic simulations in polarization-sensitive processes. Numerous efforts have been invested in developing induced dipole-based polarizable force fields. Whether additive atomic charge models or polarizable induced dipole models are used, proper parameterization of the electrostatic term plays a key role in the force field developments. In this work, we present a Python program called PyRESP for performing atomic multipole parameterizations by reproducing ab initio electrostatic potential (ESP) around molecules. PyRESP provides parameterization schemes for several electrostatic models, including the RESP model with atomic charges for the additive force fields and the RESP-ind and RESP-perm models with additional induced and permanent dipole moments for the polarizable force fields. PyRESP is a flexible and user-friendly program that can accommodate various needs during force field parameterizations for molecular modeling of any organic molecules.

Polyketides are a large class of structurally and functionally diverse natural products with important bioactivities. Many polyketides are synthesized by reducing type II polyketide synthases (PKSs), containing transiently interacting standalone enzymes. During synthesis, ketoreductase (KR) catalyzes regiospecific carbonyl to hydroxyl reduction, determining the product outcome, yet little is known about what drives specific KR–substrate interactions. In this study, computational approaches were used to explore KR–substrate interactions based on previously solved apo and mimic cocrystal structures. We found five key factors guiding KR–substrate binding. First, two major substrate binding motifs were identified. Second, substrate length is the key determinant of substrate binding position. Third, two key residues in chain length specificity were confirmed. Fourth, phosphorylation of substrates is critical for binding. Finally, packing/hydrophobic effects primarily determine the binding stability. The molecular bases revealed here will help further engineering of type II PKSs and directed biosynthesis of new polyketides.

This study investigated the impact of bromide on the formation of N-nitrosamines during chlorination and chloramination, and tried to identify the reactive intermediates responsible for variations in the yield of N-nitrosamines. As an intermediate of the reaction between bromide and HOCl, bromine chloride (BrCl) may improve the yield of N-nitrosodimethylamine (NDMA) formation. But increasing the amount of bromide added would result in BrCl being converted into HOBr, which is a weaker oxidant than HOCl. This would result in less nitrite being formed, leading to a decreased yield of NDMA via the nitrosation pathway. When NH4+, was present with the bromide during chlorination, both the rate of formation and yield of N-nitrosamines were improved markedly by highly reactive bromamines. Interestingly, bromide had an inhibitory effect on NDMA formation during the chloramination process when tertiary alkylamines, such as 3-(Dimethylaminomethyl) indole (DMAI) and trimethylamine (TMA), were used as precursors. This phenomenon provides indirect evidence for the hypothesis that the pathway of NDMA formation using tertiary amines with DMA groups is different from that of NDMA formation using secondary alkylamines.

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