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Hee-Seung Lee

Publications and source records attributed to Hee-Seung Lee.

11 recordsLinked to original sources
PubMed2007

(alpha/beta+alpha)-peptide antagonists of BH3 domain/Bcl-x(L) recognition: toward general strategies for foldamer-based inhibition of protein-protein interactions.

The development of molecules that bind to specific protein surface sites and inhibit protein-protein interactions is a fundamental challenge in molecular recognition. New strategies for approaching this challenge could have important long-term ramifications in biology and medicine. We are exploring the concept that unnatural oligomers with well-defined conformations ("foldamers") can mimic protein secondary structural elements and thereby block specific protein-protein interactions. Here, we describe the identification and analysis of helical peptide-based foldamers that bind to a specific cleft on the anti-apoptotic protein Bcl-xL by mimicking an alpha-helical BH3 domain. Initial studies, employing a fluorescence polarization (FP) competition assay, revealed that among several alpha/beta- and beta-peptide foldamer backbones only alpha/beta-peptides intended to adopt 14/15-helical secondary structure display significant binding to Bcl-xL. The most tightly binding Bcl-xL ligands are chimeric oligomers in which an N-terminal alpha/beta-peptide segment is fused to a C-terminal alpha-peptide segment ((alpha/beta + alpha)-peptides)). Sequence-affinity relationships were probed via standard and nonstandard techniques (alanine scanning and hydrophile scanning, respectively), and the results allowed us to construct a computational model of the ligand/Bcl-xL complex. Analytical ultracentrifugation with a high-affinity (alpha/beta + alpha)-peptide established 1:1 ligand:Bcl-xL stoichiometry under FP assay conditions. Binding selectivity studies with the most potent (alpha/beta + alpha)-peptide, conducted via surface plasmon resonance measurements, revealed that this ligand binds tightly to Bcl-w as well as to Bcl-xL, while binding to Bcl-2 is somewhat weaker. No binding could be detected with Mcl-1. We show that our most potent (alpha/beta + alpha)-peptide can induce cytochrome C release from mitochondria, an early step in apoptosis, in cell lysates, and that this activity is dependent upon inhibition of protein-protein interactions involving Bcl-xL.

Alanine↗
PubMed2006

Structure of liquid water at ambient temperature from ab initio molecular dynamics performed in the complete basis set limit.

Structural properties of liquid water at ambient temperature were studied using Car-Parrinello [Phys. Rev. Lett. 55, 2471 (1985)] ab initio molecular dynamics (CPAIMD) simulations combined with the Kohn-Sham (KS) density functional theory and the BLYP exchange-correlation functional for the electronic structure. Unlike other recent work on the same subject, where plane-wave (PW) or hybrid Gaussian/plane-wave basis sets were employed, in the present paper, a discrete variable representation (DVR) basis set is used to expand the KS orbitals, so that with the real-space grid adapted in the present work, the properties of liquid water could be obtained very near the complete basis set limit. Structural properties of liquid water were extracted from a 30 ps CPAIMD-BLYP/DVR trajectory at 300 K. The radial distribution functions (RDFs), spatial distribution functions, and hydrogen bond geometry obtained from the CPAIMD-BLYP/DVR simulation are generally in good agreement with the most up to date experimental measurements. Compared to recent ab initio MD simulations based on PW basis sets, less significant overstructuring was found in the RDFs and the distributions of hydrogen bond angles, suggesting that previous plane-wave and Gaussian basis set calculations have exaggerated the tendency toward overstructuring.

Journal Article↗
PubMed2006

Ab initio molecular dynamics with discrete variable representation basis sets: techniques and application to liquid water.

Finite temperature ab initio molecular dynamics (AIMD), in which forces are obtained from "on-the-fly" electronic structure calculations, is a widely used technique for studying structural and dynamical properties of chemically active systems. Recently, we introduced an AIMD scheme based on discrete variable representation (DVR) basis sets, which was shown to have improved convergence properties over the conventional plane wave (PW) basis set [Liu,Y.; et al. Phys. Rev. B 2003, 68, 125110]. In the present work, the numerical algorithms for the DVR based AIMD scheme (DVR/AIMD) are provided in detail, and the latest developments of the approach are presented. The accuracy and stability of the current implementation of the DVR/AIMD scheme are tested by performing a simulation of liquid water at ambient conditions. The structural information obtained from the present work is in good agreement with the result of recent AIMD simulations with a PW basis set (PW/AIMD). Advantages of using the DVR/AIMD scheme over the PW/AIMD method are discussed. In particular, it is shown that a DVR/AIMD simulation of liquid water in the complete basis set limit is possible with a relatively small number of grid points.

Journal Article↗
PubMed2005

Efficient evaluation of nonlocal pseudopotentials via Euler exponential spline interpolation.

An Euler exponential spline (EES) based formalism is employed to derive new expressions for the electron-atom nonlocal pseudopotential interaction (NL) in electronic structure calculations performed using a plane wave basis set that can be computed more rapidly than standard techniques. Two methods, one that is evaluated by switching between real and reciprocal space via fast Fourier transforms, and another that is evaluated completely in real space, are described. The reciprocal-space or g-space-based technique, NLEES-G, scales as NMlogM approximately N2logN, where N is the number of electronic orbitals and M is the number of plane waves. The real-space based technique, NLEES-R, scales as N2. The latter can potentially be used within a maximally spatially localized orbital method to yield linear scaling, while the former could be employed within a maximally delocalized orbital method to yield NlogN scaling. This behavior is to be contrasted with standard techniques, which scale as N3. The two new approaches are validated using several examples, including solid silicon and liquid water, and demonstrated to be improvements on other, reduced-order nonlocal techniques. Indeed, the new methods have a low overhead and become more efficient than the standard technique for systems with roughly 20 or more atoms. Both NLEES methods are shown to work stably and efficiently within the Car-Parrinello ab initio molecular dynamics framework, owing to the existence of p-2 continuous derivatives of a pth-order spline.

Journal Article↗
PubMed2005

Chimeric (alpha/beta + alpha)-peptide ligands for the BH3-recognition cleft of Bcl-XL: critical role of the molecular scaffold in protein surface recognition.

Molecules that bind to specific surface sites on proteins are of great interest from both fundamental and practical perspectives. We are exploring a ligand development strategy that is based on oligomers with discrete folding propensities ("foldamers"); we target a specific cleft on the cancer-associated protein Bcl-xL because this system is well characterized structurally. In vivo, this cleft binds to alpha-helical segments (BH3 domains) of other proteins. We evaluated several types of helical foldamer, built entirely from beta-amino acid residues or from mixtures of alpha- and beta-amino acid residues, and ultimately identified foldamers in the latter class that bind very tightly to Bcl-xL. Our results suggest that combining different types of foldamer backbones will be an effective and general strategy for creating high-affinity and specific ligands for protein surface sites.

Binding, Competitive↗
PubMed2004

Vibrational energy levels of ozone up to dissociation revisited.

Two recent papers presented calculations of the highly excited vibrational states of ozone. The nature and energies of these states may hold the key to the anomalous isotopic distribution of ozone in the atmosphere. Even though the same potential energy surface of Babikov et al. was used in both calculations, the number of bound van der Waals states reported below dissociation differed significantly. In order to resolve the issue we present here the results of an independent computation of all the bound vibrational states of (16)O(16)O(16)O and (16)O(16)O(18)O up to dissociation. Our methods differ from both earlier calculations since we use hyperspherical coordinates and a direct product discrete variable representation of the Hamiltonian. The results of present work support the existence of several van der Waals states for J=0 on this potential energy surface.

Journal Article↗
PubMed2004

Iterative solutions with energy selected bases for highly excited vibrations of tetra-atomic molecules.

The use of energy selected bases (ESB) with iterative diagonalization of the Hamiltonian matrix is described for vibrations of tetra-atomic systems. The performance of the method is tested by computing vibrational states of HOOH below 10,000 cm(-1) (1296 A+ symmetry states) and H(2)CO below 13,500 cm(-1) (729 A(1) symmetry states). For iterative solutions, we tested both the implicitly restarted Lanczos method (IRLM) and the standard (nonreorthogonalizing) Lanczos approach. Comparison with other contracted basis approach as well as direct product grid representation shows superior performance of the ESB/IRLM approach. Of the two systems, H(2)CO is found to be more challenging than HOOH since it has much stronger couplings among vibrational modes, which leads to a drastically larger primitive basis set. For H(2)CO we also discuss some interesting behavior of the molecule in the high internal energy regime.

Journal Article↗
PubMed2003

Accommodation of alpha-substituted residues in the beta-peptide 12-helix: expanding the range of substitution patterns available to a foldamer scaffold.

Beta-amino acid oligomers composed exclusively of homochiral trans-2-aminocyclopentanecarboxylic acid (ACPC) residues and/or related pyrrolidine-based residues are known to favor a specific helical secondary structure that is defined by 12-membered ring C=O(i)- -H-N(i+3) hydrogen bonds ("12-helix"). The 12-helix is structurally similar to the familiar alpha-helix and therefore represents a source of potential alpha-helix-mimics. The 12-helix will be most useful in this regard if this conformational scaffold can be employed to arrange specific sets of protein-like side chains in space. Here we examine whether the 12-helix tolerates insertion of acyclic beta-amino acid residues bearing a substituent in the alpha-position ("beta(2)-residues"). Seventeen homologous beta-peptide heptamers have been prepared in which one to four beta(2)-residues reside among ACPC and/or pyrrolidine residues. Circular dichroism comparisons suggest that beta(2)-residues have a lower 12-helical propensity than do residues preorganized by a five-membered ring, as expected, but that beta-peptides containing beta(2)-residues at one or two of the seven positions retain a significant preference for 12-helix formation. These results indicate that a limited number of beta(2)-residues can be used to introduce side chains at specific positions along the surface of a 12-helix.

Circular Dichroism↗
PubMed2003

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones.

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.

Amino Acids↗
PubMed2002

A fluorescence polarization assay for the identification of inhibitors of the p53-DM2 protein-protein interaction.

Improper function of the tumor suppressor protein p53 is a contributing factor in many human cancers. In normal cells, p53 acts to arrest the cell cycle in response to DNA damage or nucleotide depletion. One mechanism of regulating the amount of p53 in the cell is through the action of the Double Minute 2 protein, DM2 (also known as MDM2), which ubiquitinates p53 and targets it for proteosomal degradation. In a number of human cancers, the DM2 gene is amplified or overexpressed, leading to inadequate levels of p53 for cell cycle arrest or apoptosis. With the goal of restoring p53 function in cancers that overexpress DM2, we are developing inhibitors of the p53-DM2 protein-protein interaction that structurally mimic the N-terminal segment of p53 that binds to DM2. To assist this effort, we have devised a fluorescence polarization assay that quantifies the interaction between the N-terminal regions of both proteins in 384-well microtiter plates. Using this assay, we have demonstrated that a peptide with a nonhydrolyzable beta-amino acid substitution binds DM2 with an affinity comparable to a p53 peptide that is composed of only alpha-amino acids.

Amino Acid Sequence↗