Biomedical subjects
Publications and source records attributed to Sangyoub Lee.
A peptide-cleaving catalyst selective for peptide deformylase (PDF) was obtained from a library containing about 15 000 catalyst candidates. The catalyst cleaved the polypeptide backbone of PDF at Gln(152)-Arg(153). Docking simulations suggested multiple modes of interactions in the complex formed between the catalyst and PDF.
Comparative protein structure modeling and free energy perturbation simulation have been applied in a consecutive manner to investigate the mutation-induced stabilization of membrane proteins (MPs) in aqueous solution without knowledge of their three-dimensional structures. The calculated difference in protein solvation free energy between the wild type and a mutant compares well with their relative thermodynamic stabilities in solution. For monomeric MPs, a mutant reveals a higher stability than the wild type if the calculated solvation free energy indicates a favorable change. On the contrary, for oligomeric MPs the stability of a mutant increases as the solvation free energy of a mutated monomer becomes less favorable, indicating that the oligomeric MP mutant would be stabilized in solution due to the reduced desolvation cost for oligomerization. The present computational strategy is expected to find its way as a useful tool for assessing the relative stability of a mutant MP with respect to its wild type in solution.
Based on the optimized Rouse-Zimm (ORZ) approximation to the Kirkwood diffusion equation, we investigate the effects of excluded volume interactions on the single chain dynamics. By incorporating the nonuniformly expanded moments of interbead distances into the expressions for the diffusion and structure matrices appearing in the ORZ diffusion equation, we obtain the general relaxation spectrum for flexible chains that is valid over the range from theta; solvents to good solvents. The present theory involves four parameters: the Kuhn statistical length b(0), the bead number N, the excluded volume parameter z, and the hydrodynamic interaction parameter h(*). These model parameters are determined from structural data of polymers with the aid of the quasi-two-parameter theory. The set of relaxation times of ORZ normal modes calculated with these bead-and-spring model parameters enables the theoretical prediction of various frictional and dynamical properties of polymers within a unified framework. The present ORZ theory generalizes the Ptitsyn-Eizner-type approaches by incorporating the nonuniform chain expansion effect into the structure matrix as well as the diffusion matrix.
The design and discovery of selective cyclin-dependent kinase 4 (CDK4) inhibitors have been actively pursued in order to develop therapeutic cancer treatments. By means of a consecutive computational protocol involving homology modeling, docking experiments, and molecular dynamics simulations, we examine the characteristic structural and dynamic properties that distinguish CDK4 from CDK2 in its complexation with selective inhibitors. The results for all three CDK4-selective inhibitors under investigation show that the large-amplitude motion of a disordered loop of CDK4 is damped out in the presence of the inhibitors whereas their binding in the CDK2 active site has little effect on the loop flexibility. It is also found that the binding preference of CDK4- selective inhibitors for CDK4 over CDK2 stems from the reduced solvent accessibility in the active site of the former due to the formation of a stable hydrogen-bond triad by the Asp99, Arg101, and Thr102 side chains at the top of the active-site gorge. Besides the differences in loop flexibility and solvent accessibility, the dynamic stabilities of the hydrogen bonds between the inhibitors and the side chain of the lysine residue at the bottom of the active site also correlate well with the relative binding affinities of the inhibitors for the two CDKs. These results highlight the usefulness of this computational approach in evaluating the selectivity of a CDK inhibitor, and demonstrate the necessity of considering protein flexibility and solvent effects in designing new selective CDK4-selective inhibitors.
We present a molecular dynamics (MD) simulation method for calculating the diffusion-influenced reaction rates in the limit of low reactant concentrations. To calculate the reaction rate coefficient, we use MD trajectories of a nonreactive equilibrium system that are initiated with a pair of reactant molecules in reactive configuration. Hence reaction systems involving complicated reactant molecules with geometrically restricted reactivities can be treated with comparable efficiency as the simple hard-sphere reaction system. Compared to the similar MD method proposed by Van Beijeren, Dong, and Bocquet [J. Chem. Phys. 114, 6265 (2001)], the present method has a couple of advantages. First, reactions involving more general sink functions can be treated. Second, more accurate results can be obtained when the reaction probability upon collision is less than unity. As an application, we investigate the effects of nondiffusive dynamics and hydrodynamic interaction of reactants on the reaction rate.
As an effort to develop therapeutics for cancer treatments, a number of effective histone deacetylase inhibitors with structural diversity have been discovered. To gain insight into optimizing the activity of an identified lead compound, a computational protocol sequentially involving homology modeling, docking experiments, molecular dynamics simulation, and free energy perturbation calculations was applied for rationalizing the relative activities of known histone deacetylase inhibitors. With the newly developed force field parameters for the coordination environment of the catalytic zinc ion in hand, the computational strategy proved to be successful in predicting the rank orders for 12 derivatives of three hydroxamate-based inhibitor scaffolds with indole amide, pyrrole, and sulfonamide moieties. The results showed that the free energy of an inhibitor in aqueous solution should be an important factor in determining the binding free energy. Hence, in order to enhance the inhibitory activity by adding or substituting a chemical group, the increased stabilization in solution due to the structural changes must be overcome by a stronger enzyme-inhibitor interaction. It was also found that to optimize inhibitor potency, the hydrophobic head of an inhibitor should be elongated or enlarged so that it can interact with Pro29 and His28 that are components of the flexible loop at the top of the active site.
Memapsin 2 (BACE) is an aspartyl protease known as beta-secretase that acts on the production of the beta-amyloid peptide in the human brain, a key event in the pathogenesis of Alzheimer's disease. Although it is expected that the net charge of the catalytic Asp diad would be -1 as in other kinds of aspartyl proteases, the exact protonation states of Asp32 and Asp228 have not been known without ambiguity. Two independent molecular dynamics (MD) simulations of BACE in complex with the potent inhibitor OM99-2 are carried out to determine the preferred protonation state of the Asp diad in the context that is consistent with the previous X-ray crystal structure. The results show that a strong hydrogen bond between the inhibitor hydroxyl group and Asp228 can be maintained only when Asp32 is neutral and Asp228 is ionized. The preference of this protonation state is further supported from the energetic and structural features found in the docking experiment of a novel potent inhibitor with the BACE active site. Thus, both MD and docking studies suggest that the role of hydrogen bond acceptor for the hydroxyl and piperazine groups of the inhibitors should be played by Asp228 instead of Asp32. This may be a key piece of information for the structure-based design/discovery of new inhibitor drugs.