The crystal structure of an efficient Diels-Alder antibody catalyst at 1.9 angstrom resolution reveals almost perfect shape complementarity with its transition state analog. Comparison with highly related progesterone and Diels-Alderase antibodies that arose from the same primordial germ line template shows the relatively subtle mutational steps that were able to evolve both structural complementarity and catalytic efficiency.

A highly specific Diels-Alder protein catalyst was made by manipulating the antibody repertoire of the immune system. The catalytic antibody 13G5 catalyzes a disfavored exo Diels-Alder transformation in a reaction for which there is no natural enzyme counterpart and that yields a single regioisomer in high enantiomeric excess. The crystal structure of the antibody Fab in complex with a ferrocenyl inhibitor containing the essential haptenic core that elicited 13G5 was determined at 1.95 angstrom resolution. Three key antibody residues appear to be responsible for the observed catalysis and product control. Tyrosine-L36 acts as a Lewis acid activating the dienophile for nucleophilic attack, and asparagine-L91 and aspartic acid-H50 form hydrogen bonds to the carboxylate side chain that substitutes for the carbamate diene substrate. This hydrogen-bonding scheme leads to rate acceleration and also pronounced stereoselectivity. Docking experiments with the four possible ortho transition states of the reaction explain the specific exo effect and suggest that the (3R,4R)-exo stereoisomer is the preferred product.

Traditionally, computing the binding affinities of proteins to even relatively small and rigid ligands by free-energy methods has been challenging due to large computational costs and significant errors. Here, we apply a new molecular simulation acceleration method called MELD (Modeling by Employing Limited Data) to study the binding of stapled α-helical peptides to the MDM2 and MDMX proteins. We employ free-energy-based molecular dynamics simulations (MELD-MD) to identify binding poses and calculate binding affinities. Even though stapled peptides are larger and more complex than most protein ligands, the MELD-MD simulations can identify relevant binding poses and compute relative binding affinities. MELD-MD appears to be a promising method for computing the binding properties of peptide ligands with proteins.

Developing an effective means for the real-time probing of amyloid β (Aβ) that is closely implicated in Alzheimer's disease (AD) could help better understand and monitor the disease. Here we describe an economic approach based on the simple composition of a natural product, resveratrol (Res), with graphene oxide (GO) for the rapid, fluorogenic recognition of Aβ. The Res@GO composite has proved specific for Aβ over a range of proteins and ions, and could sensitively capture both Aβ monomers and fibers in a physiological buffer solution within only 3 min. The composite can also fluorescently image amyloid deposits in a mouse brain section within 30 min. This new protocol is much cheaper and more timesaving than the conventional immunofluorescence staining technique employed clinically, providing an economic tool for the concise detection of AD.

The transition structures for the ene reactions of cyclopropene with ethylene, propene, and cyclopropene have been located with ab initio molecular orbital calculations and the 6-31G* basis set and by DFT calculations with the Becke3LYP functional and the 6-31G* basis set. Several of the transition structures have also been located with CASSCF calculations. Energies of all stationary points were also evaluated with second-order Møller-Plesset theory using the RHF/6-31G* optimized geometry. The geometries of each transition structure and the energetics of each reaction are discussed and compared to the ene reaction of propene with ethylene. Calculations show that the cyclopropene ene reactions have much lower activation barriers than the propene-ethylene ene reaction, in agreement with experimental results. The transition structures have varying degrees of asynchronicity. The stabilities of the possible radical intermediates for each reaction are reflected in the geometries of the transition structures. The relief of strain in a cyclopropene, when acting as the enophile, accounts for the energetic differences in these reactions. The endo transition structure for the dimerization is lower in energy than the exo transition structure by 2.7 kcal/mol at the Becke3LYP/6-31G* + ZPE level of theory. Secondary orbital overlap of a CH bond of the enophile with the π-system at the central carbon of the ene is proposed to account for the preference for the endo transition structure. Barely stable diradical intermediates have been found for both endo and exo cyclopropene dimerization reactions, but it is likely that they are artifacts of the current level of theory.