A conformational analysis and docking study of nitrophenoxyalkylbenzylamine derivatives with inhibitory activities against acethylcholinesterase was carried out in an attempt to analyze their structure-activity relationships based on the enzyme-inhibitor interaction. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by molecular dynamics. Next, a docking study of the inhibitors into the ligand binding site was performed. Among the resulting stable complex structures, it was found that in the case of the two stereoisomers with a 7-membered ring, the more active one of the two formed a much more stable complex structure. On the other hand, complex structures with comparable energies were obtained for both stereoisomers that had no 7-membered ring and showed similar inhibitory activities. Lastly, structural features of the complex models of a series of inhibitors with side chains of different lengths were evaluated and corresponded well to their inhibitory activities.

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By using the method to define a local structural motif of proteins by the Delaunay tessellation proposed by Wako and Yamato (Protein Eng. 11, 981-990 (1998)), we analyzed environment-dependent and position-specific frequencies of amino-acid occurrences in α-helices. In that method the three-dimensional structure of a protein molecule is uniquely divided into non-overlapping Delaunay tetrahedrons, each vertex of which is occupied by one of the comprising residues. A code is then assigned to each tetrahedron so as to characterize the local structure containing it. The tetrahedrons located in the interior of the α-helices are assigned 36 kinds of codes. The differences in the codes reflect the existence and absence of four residues surrounding the relevant region of the α-helix. In other words, the environment of the α-helix can be differentiated by these codes. Accordingly, we analyzed the frequencies of amino acid occurrences on each vertex of the tetrahedrons for each of these codes. Such data provide information about possible amino acid substitutions specific to a vertex position (i.e., a position in the α-helix) for a given code (i.e., environment around the α-helix). Furthermore, the principal component analysis was carried out to reveal general features of the amino acid occurrences in the α-helices. In relation to these results, such frequencies at the N- and C-terminals of the α-helix are also discussed.

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In the previous paper (O. Kitao and T. Ogawa, Mol. Phys., 101, 3-17 (2003).), we have proposed the consistent charge equilibration (CQEq) method. The CQEq energy term was combined with the universal force field (UFF) to develop the CQEq with UFF (CUFF). In this article, to confirm the accuracy of the CUFF, geometry optimizations by the CUFF were performed for a series of amino acid molecules. The CUFF can well reproduce the HF/6-31G ^** geometries aside from some flexible dihedral angles. The partial charges obtained by the CQEq deviate somewhat from those by the restrained electrostatic potential fit; this result suggested us a way to improve the CQEq and the CUFF.

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We have performed molecular dynamics simulations on the human prion protein to study the effect of point mutations in relation to the inherited form of Creutzfeldt-Jakob disease. Three model structures of the human prion protein are examined with a focus on their dynamics and conformational changes. Model 1 is an NMR structure of the globular domain (125-228) of a wild-type prion. The model consists of three α-helices and an anti-parallel β-sheet. Models 2 and 3 are mutant structures containing a Glu200→Asp and a Glu200→Lys substitution, respectively. These models are derived from NMR structures. The Glu200→Lys in model 3 is a disease-related amino acid exchange. The results of about 2-million time step calculations have shown that the globular domains of models 1 and 2 are stable, whereas, for model 3, we observe a partial unfolding and reorganization of the protein structure by insertion of the disease-related mutation Glu200→Lys.

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