Showing papers by "Kaixian Chen published in 2004"

The Multiplicity, Strength, and Nature of the Interaction of Nucleobases with Alkaline and Alkaline Earth Metal Cations: A Density Functional Theory Investigation

Abstract: Density functional theory (DFT) calculations were performed at the B3LYP/6-311++G(d,p) level to systematically explore the geometrical multiplicity and binding strength for the complexes formed by alkaline and alkaline earth metal cations, viz. Li+, Na+, K+, Be2+, Mg2+, and Ca2+ (Mn+, hereinafter), with nucleobases, namely, adenine, cytosine, guanine, thymine, and uracil. Morokuma decomposition and orbital analysis were used to analyze the binding components. A total of 150 initial structures were designed and optimized, of which 93 optimized structures were found, which could be divided into two different types: cation−π complex and cation−heteroatom complex. In the former, a Mn+ is located above the nucleobase ring, while in the latter a Mn+ directly interacts in flank with the heteroatom(s) of a nucleobase. The strongest binding of −319.2 kcal/mol was found in the Be2+−guanine complex. Furthermore, the planar ring structures of the nucleobases in some cation−π complexes were deformed, destroying more ...

Binding analyses between Human PPARgamma-LBD and ligands.

Abstract: The binding characteristics of a series of PPARgamma ligands (GW9662, GI 262570, cis-parinaric acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), LY171883, indomethacin, linoleic acid, palmitic acid and troglitazone) to human PPARgamma ligand binding domain have been investigated for the first time by using surface plasmon resonance biosensor technology, CD spectroscopy and molecular docking simulation. The surface plasmon resonance biosensor determined equilibrium dissociation constants (KD values) are in agreement with the results reported in the literature measured by other methods, indicating that the surface plasmon resonance biosensor can assume a direct assay method in screening new PPARgamma agonists or antagonists. Conformational changes of PPARgamma caused by the ligand binding were detected by CD determination. It is interesting that the thermal stability of the receptor, reflected by the increase of the transition temperature (T(m)), was enhanced by the binding of the ligands. The increment of the transition temperature (DeltaT(m)) of PPARgamma owing to ligand binding correlated well with the binding affinity. This finding implies that CD could possibly be a complementary technology with which to determine the binding affinities of ligands to PPARgamma. Molecular docking simulation provided reasonable and reliable binding models of the ligands to PPARgamma at the atomic level, which gave a good explanation of the structure-binding affinity relationship for the ligands interacting with PPARgamma. Moreover, the predicted binding free energies for the ligands correlated well with the binding constants measured by the surface plasmon resonance biosensor, indicating that the docking paradigm used in this study could possibly be employed in virtual screening to discover new PPARgamma ligands, although the docking program cannot accurately predict the absolute ligand-PPARgamma binding affinity.

Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis.

Abstract: AIM: Based on the structural analysis to reveal the mechanism of ligand binding to beta-secretase and the specificity of each binding sub-site. METHODS: Molecular dynamics was used to simulate on the ligand free beta-secretase and ligand bound beta-secretase. The trajectories were analyzed using the essential dynamics, and the significant conformational change was illustrated employing the DynDom program. RESULTS: The essential dynamics and DynDom analyses clearly showed that the beta-secretase experienced a large conformational change upon the substrate or inhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate the ligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysis revealed that residues at P2, P1, and P1' positions of the inhibitor were very important for the binding, and residues at P2' and P3' positions may be modified to improve the binding specificity. S3 subsite of the enzyme still had space to modify the inhibitors in increasing the binding affinity. CONCLUSION: The information presented here is valuable and could be used to identify small molecular inhibitors of beta-secretase.

A common intermediate for prebiotic synthesis of proteins and nucleosides: a density functional theory (DFT) study on the formation of penta-coordinate phosphorus carboxylic–phosphoric mixed anhydride from N-phosphoryl amino acids

Abstract: N -phosphoryl amino acids (PAA) are a unique chemical species with many chemical reactivities and properties, including the ability to self-assemble into oligopeptides. Because of their chemical characteristics, they have been proposed as the common origin for both nucleic acids and proteins. In this paper, we discussed six intramolecular mixed carboxylic–phosphoric anhydrides (IMCPAs) as possible intermediates for the prebiotic synthesis of biopolymers from PAA. We also investigated the role of water molecules in the formation of IMCPA using density functional theory B3LYP quantum mechanical calculations at the 6-31G** and 6-311+G** levels. Our results showed that the energy barrier of IMCPA formation was reduced from 19.5 kcal mol −1 to 9.9 kcal mol −1 when water participation and solvent effects were considered. Thus, the direct participation of one water molecule and the bulk solvent effects both play important roles in the formation of IMCPA.

Steered molecular dynamics simulations of protein-ligand interactions

Abstract: Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dynamics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be accessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of binding and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.

Simulating the interactions of toxins with K+ channels.

Abstract: Toxins have been important tools to characterize the structures and functions of K+ channels in recent years due to their unique blockage of the K+ current and other physiological functions to the K+ channels, especially the voltage-gated K+ channels. Knowledge of the interacting surfaces between the toxins and the channels has been accumulated both from biological explorations and theoretical simulations. It has been found that the electrostatic potentials act as the driving force for the recognition of the toxins with the channels, and the orientation of the toxins over the channels follows the direction of the dipole moment. The binding site is composed most of the conservative residues of the negatively charged rings of Asp/Glu and residues around the edge of the central pore. The selectivity mainly comes from the type and distribution of the positive charged residues, and the whole topologies of the toxins. Based on the molecular determinants of the complex formation, and taking advantage of the structure-based methodologies of molecular design, it is hopefully to develop new generation of lead compounds specifically binding with subtypes of K+ channels.

Sars coronaviruses 3cl protease 3d-structure model and anti-sars medicines

Abstract: The present invention discloses 3D-structure of SARS-CoV Viruses 3CL Protease obtained through molecular modeling: The 3D-structure can be used as a target for screening medical database CMC (Comprehensive Medicinal Chemistry, MDL Information System, Inc.), discovering a group of compounds which have activity of inhibiting SARS-CoV viruses 3CL Protease. Cinanserin is assayed on molecular and viruse levels, discovering that it has better activity of inhibiting SARS-CoV viruses 3CL Protease and it has anti-SARS-CoV viruses activity. Cinanserin analogs are synthesized. We did assay on molecular and viruses levels, discovering that they have activity of inhibiting SARS-CoV viruses 3CL Protease and they have anti-SARS-CoV viruses activity, which can be used for treating and/or preventing SARS-CoV viruses infection.