No abstract

The Src-homology-3 (SH3) domain of the Caenorhabditis elegans protein Sem-5 binds proline-rich sequences. It is reported that the SH3 domains broadly accept amide N-substituted residues instead of only recognizing prolines on the basis of side chain shape or rigidity. We have studied the interactions between Sem-5 and its ligands using molecular dynamics (MD), free energy calculations, and sequence analysis. Relative binding free energies, estimated by a method called MM/PBSA, between different substitutions at sites -1, 0, and +2 of the peptide are consistent with the experimental data. A new method to calculate atomic partial charges, AM1-BCC method, is also used in the binding free energy calculations for different N-substitutions at site -1. The results are very similar to those obtained from widely used RESP charges in the AMBER force field. AM1-BCC charges can be calculated more rapidly for any organic molecule than can the RESP charges. Therefore, their use can enable a broader and more efficient application of the MM/PBSA method in drug design. Examination of each component of the free energy leads to the construction of van der Waals interaction energy profiles for each ligand as well as for wild-type and mutant Sem-5 proteins. The profiles and free energy calculations indicate that the van der Waals interactions between the ligands and the receptor determine whether an N- or a Calpha-substituted residue is favored at each site. A VC value (defined as a product of the conservation percentage of each residue and its van der Waals interaction energy with the ligand) is used to identify several residues on the receptor that are critical for specificity and binding affinity. This VC value may have a potential use in identifying crucial residues for any ligand-protein or protein-protein system. Mutations at two of those crucial residues, N190 and N206, are examined. One mutation, N190I, is predicted to reduce the selectivity of the N-substituted residue at site -1 of the ligand and is shown to bind similarly with N- and Calpha-substituted residues at that site.

Molecular stacking modes, generally classified as H-, J-, and X-aggregation, play a key role in determining the optoelectronic properties of organic crystals. However, the control of stacking transformation of a specific molecule is an unmet challenge, and a priori prediction of the performance in different stacking modes is extraordinarily difficult to achieve. In particular, the existence of hybrid stacking modes and their combined effect on physicochemical properties of molecular crystals are not fully understood. Herein, unexpected stacking transformation from H- to J- and X-aggregation is observed in the crystal structure of a small heterocyclic molecule, 4,4′-bipyridine (4,4′-Bpy), upon coassembly with N -acetyl- l -alanine (AcA), a nonaromatic amino acid derivative. This structural transformation into hybrid stacking mode improves physicochemical properties of the cocrystals, including a large red-shifted emission, enhanced supramolecular chirality, improved thermal stability, and higher mechanical properties. While a single crystal of 4,4′-Bpy shows good optical waveguiding and piezoelectric properties due to the uniform elongated needles and low symmetry of crystal packing, the significantly lower band gap and resistance of the cocrystal indicate improved conductivity. This study not only demonstrates cocrystallization-induced packing transformation between H-, J-, and X-aggregations in the solid state, leading to tunable mechanical and optoelectronic properties, but also will inspire future molecular design of organic functional materials by the coassembly strategy.

The β-amyloid cleaving enzymes 1 and 2 (BACE1 and BACE2) have been regarded as the prospective targets for clinically treating Alzheimer's disease (AD) in the last two decades. Thus, insight into the binding differences of inhibitors to BACE1 and BACE2 is of significance for designing highly selective inhibitors toward the two proteins. In this work, multiple short molecular dynamics (MSMD) simulations are coupled with the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding selectivity of three inhibitors DBO, CS9, and SC7 on BACE1 over BACE2. The results show that the entropy effect plays a key role in selectivity identification of inhibitors toward BACE1 and BACE2, which determines that DBO has better selectivity toward BACE2 over BACE1, while CS9 and CS7 can more favorably bind to BACE1 than BACE2. The hierarchical clustering analysis based on energetic contributions of residues suggests that BACE1 and BACE2 share the common hot interaction spots. The residue-based free-energy decomposition method was applied to compute the inhibitor−residue interaction spectrum, and the results recognize four common binding subpockets corresponding to the different groups of inhibitors, which can be used as efficient targets for designing highly selective inhibitors toward BACE1 and BACE2. Therefore, these results provide a useful molecular basis and dynamics information for development of highly selective inhibitors targeting BACE1 and BACE2.