Although recognized in small molecules for quite some time, the implications of halogen bonding in biomolecular systems are only now coming to light. In this study, several systems of proteins in complex with halogenated ligands have been investigated by using a two-layer QM/MM ONIOM methodology. In all cases, the halogen-oxygen distances are shown to be much less than the van der Waals radius sums. Single-point energy calculations unveil that the interaction becomes comparable in magnitude to classical hydrogen bonding. Furthermore, we found that the strength of the interactions attenuates in the order H approximately I > Br > Cl. These results agree well with the characteristics discovered within small model halogen-bonded systems. A detailed analysis of the interactions reveals that halogen bonding interactions are responsible for the different conformation of the molecules in the active site. This study would help to establish such interaction as a potential and effective tool in the context of drug design.

Halogenation is an important approach in lead optimization for drug development and about half of the molecules used in high-throughput screening are halogenated. However, there is neither a suitable theoretical algorithm for evaluating the interaction between the halogen atoms of a ligand and its target protein nor a detailed understanding of how a halogen atom interacts with electron-rich atoms or groups of the residues in the binding pocket. In this Perspective, we concentrate on nonbonding interactions of halogens from both crystallographic data and theoretical viewpoints. It is found that organic halogen atoms are favorably involved in a wide variety of noncovalent protein-ligand interactions, such as halogen bonds C-X...O and hydrogen bonds C-X...H, that show remarkable differences in terms of the geometrical and energetic features. In biological molecules, heavier halogens prefer to form linear interactions with oxygen atoms and aromatic pi systems as compared to N or S, while the mean intermolecular distances for these types of halogen bonds increase with the radius or polarizability of halogen atoms, viz., Cl < Br < I. Furthermore, F...H interactions in protein-ligand complexes exhibit disparate behavior relative to X...H (X = Cl, Br, I) counterparts. These observed tendencies of the interactions involving halogens are subsequently rationalized by means of ab initio calculations using small model systems. The results presented herein should be of great use in the rational design of halogenated ligands as inhibitors and drugs as well as in biological engineering.

Halogen bond has attracted a great deal of attention in the past years for hit-to-lead-to-candidate optimization aiming at improving drug-target binding affinity. In general, heavy organohalogens (i.e., organochlorines, organobromines, and organoiodines) are capable of forming halogen bonds while organofluorines are not. In order to explore the possible roles that halogen bonds could play beyond improving binding affinity, we performed a detailed database survey and quantum chemistry calculation with close attention paid to (1) the change of the ratio of heavy organohalogens to organofluorines along the drug discovery and development process and (2) the halogen bonds between organohalogens and nonbiopolymers or nontarget biopolymers. Our database survey revealed that (1) an obviously increasing trend of the ratio of heavy organohalogens to organofluorines was observed along the drug discovery and development process, illustrating that more organofluorines are worn and eliminated than heavy organohalogens during the process, suggesting that heavy halogens with the capability of forming halogen bonds should have priority for lead optimization; and (2) more than 16% of the halogen bonds in PDB are formed between organohalogens and water, and nearly 20% of the halogen bonds are formed with the proteins that are involved in the ADME/T process. Our QM/MM calculations validated the contribution of the halogen bond to the binding between organohalogens and plasma transport proteins. Thus, halogen bonds could play roles not only in improving drug-target binding affinity but also in tuning ADME/T property. Therefore, we suggest that albeit halogenation is a valuable approach for improving ligand bioactivity, more attention should be paid in the future to the application of the halogen bond for ligand ADME/T property optimization.

The amyloid ␤-peptides (A␤s), containing 39 -43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of A␤40, 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an ␣-helix to ␤-sheet conformational transition for A␤40 was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with ␤-sheet components were observed as intermediates in the unfolding pathway of A␤40. Four glycines (G25, G29, G33, and G37) are important for A␤40 to form ␤-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the ␤-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of A␤40 is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for A␤40 aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of A␤ and amyloid fibril formation. molecular dynamics simulation A lzheimer's disease (AD), a neurodegenerative disorder, is pathologically characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles in the brain (1). The major components of the plaques are amyloid ␤-peptides (A␤s) consisting of 39-43 residues that are proteolytically derived from the widely distributed transmembrane amyloid precursor glycoprotein (APP) (2-4). The amyloid hypothesis suggests that misfolding of A␤ leads to its dysfunctions and fibrillization; the latter is associated with a cascade of neuropathogenetic events to produce the cognitive and behavioral decline hallmarks of AD (4-6). Recently, however, compelling evidence has emerged that not the fibrillar aggregates but the dominant ␤-sheet structure of oligomers and fibril intermediates (protofibrils) are neurotoxic and might be the determinant pathogenic factor in AD (7-9). For example, Walsh et al. (8) demonstrated that cerebral microinjection of cell medium containing abundant A␤ monomers and oligomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation in rats in vivo. The conflict between the amyloid hypothesis and these new emerging experimental observations has stimulated more and more researchers to study the earliest phases of A␤ assembly and to explore the intrinsic properties of A␤s and the conformational dynamic behaviors of the A␤ monomer (9-15).In addition, it has been established experimentally that the major secondary structure adopted by A␤ depends on the environment. The A␤ monomer favors an ␣-helix structure in a me...