Biomedical subjects

Lee-Wei Yang

Publications and source records attributed to Lee-Wei Yang.

6 recordsLinked to original sources

PubMed2006

Anisotropic network model: systematic evaluation and a new web interface.

MOTIVATION: The Anisotropic Network Model (ANM) is a simple yet powerful model for normal mode analysis of proteins. Despite its broad use for exploring biomolecular collective motions, ANM has not been systematically evaluated to date. A lack of a convenient interface has been an additional obstacle for easy usage. RESULTS: ANM has been evaluated on a large set of proteins to establish the optimal model parameters that achieve the highest correlation with experimental data and its limits of accuracy and applicability. Residue fluctuations in globular proteins are shown to be more accurately predicted than those in nonglobular proteins, and core residues are more accurately described than solvent-exposed ones. Significant improvement in agreement with experiments is observed with increase in the resolution of the examined structure. A new server for ANM calculations is presented, which offers flexible options for controlling model parameters and output formats, interactive animation of collective modes and advanced graphical features. AVAILABILITY: ANM server (http://www.ccbb.pitt.edu/anm)

Algorithms↗

PubMed2006

oGNM: online computation of structural dynamics using the Gaussian Network Model.

An assessment of the equilibrium dynamics of biomolecular systems, and in particular their most cooperative fluctuations accessible under native state conditions, is a first step towards understanding molecular mechanisms relevant to biological function. We present a web-based system, oGNM that enables users to calculate online the shape and dispersion of normal modes of motion for proteins, oligonucleotides and their complexes, or associated biological units, using the Gaussian Network Model (GNM). Computations with the new engine are 5-6 orders of magnitude faster than those using conventional normal mode analyses. Two cases studies illustrate the utility of oGNM. The first shows that the thermal fluctuations predicted for 1250 non-homologous proteins correlate well with X-ray crystallographic data over a broad range [7.3-15 A] of inter-residue interaction cutoff distances and the correlations improve with increasing observation temperatures. The second study, focused on 64 oligonucleotides and oligonucleotide-protein complexes, shows that good agreement with experiments is achieved by representing each nucleotide by three GNM nodes (as opposed to one-node-per-residue in proteins) along with uniform interaction ranges for all components of the complexes. These results open the way to a rapid assessment of the dynamics of DNA/RNA-containing complexes. The server can be accessed at http://ignm.ccbb.pitt.edu/GNM_Online_Calculation.htm.

Algorithms↗

PubMed2005

Elastic network models for understanding biomolecular machinery: from enzymes to supramolecular assemblies.

With advances in structure genomics, it is now recognized that knowledge of structure alone is insufficient to understand and control the mechanisms of biomolecular function. Additional information in the form of dynamics is needed. As demonstrated in a large number of studies, the machinery of proteins and their complexes can be understood to a good approximation by adopting Gaussian (or elastic) network models (GNM) for simplified normal mode analyses. While this approximation lacks chemical details, it provides us with a means for assessing the collective motions of large structures/assemblies and perform a comparative analysis of a series of proteins, thus providing insights into the mechanical aspects of biomolecular dynamics. In this paper, we discuss recent applications of GNM to a series of enzymes as well as large structures such as the HK97 bacteriophage viral capsids. Understanding the dynamics of large protein structures can be computationally challenging. To this end, we introduce a new approach for building a hierarchical, reduced rank representation of the protein topology and consequently the fluctuation dynamics.

Bacteriophages↗

PubMed2005

iGNM: a database of protein functional motions based on Gaussian Network Model.

MOTIVATION: The knowledge of protein structure is not sufficient for understanding and controlling its function. Function is a dynamic property. Although protein structural information has been rapidly accumulating in databases, little effort has been invested to date toward systematically characterizing protein dynamics. The recent success of analytical methods based on elastic network models, and in particular the Gaussian Network Model (GNM), permits us to perform a high-throughput analysis of the collective dynamics of proteins. RESULTS: We computed the GNM dynamics for 20 058 structures from the Protein Data Bank, and generated information on the equilibrium dynamics at the level of individual residues. The results are stored on a web-based system called iGNM and configured so as to permit the users to visualize or download the results through a standard web browser using a simple search engine. Static and animated images for describing the conformational mobility of proteins over a broad range of normal modes are accessible, along with an online calculation engine available for newly deposited structures. A case study of the dynamics of 20 non-homologous hydrolases is presented to illustrate the utility of the iGNM database for identifying key residues that control the cooperative motions and revealing the connection between collective dynamics and catalytic activity.

Algorithms↗

PubMed2005

Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes.

Growing evidence supports the view that enzymatic activity results from a subtle interplay between chemical kinetics and molecular motions. A systematic analysis is performed here to delineate the type and level of coupling between catalysis and conformational mechanics. The dynamics of a set of 98 enzymes representative of different EC classes are analyzed with the Gaussian network model (GNM) and compared with experimental data. In more than 70% of the examined enzymes, the global hinge centers predicted by the GNM are found to be colocalized with the catalytic sites experimentally identified. Low translational mobility (< 7%) is observed for the catalytic residues, consistent with the fine-tuned design of enzymes to achieve precise mechanochemical activities. Ligand binding sites, while closely neighboring catalytic sites, enjoy a moderate flexibility to accommodate the ligand binding. These findings could serve as additional criteria for assessing drug binding residues and could lessen the computational burden of substrate docking searches.

Binding Sites↗

PubMed2002

Insight into the activation mechanism of Escherichia coli octaprenyl pyrophosphate synthase derived from pre-steady-state kinetic analysis.

Octaprenyl pyrophosphate synthase (OPPs) catalyzes the sequential condensation of five molecules of isopentenyl pyrophosphate with farnesyl pyrophosphate to generate all-trans C40-octaprenyl pyrophosphate, which constitutes the side chain of ubiquinone. Due to the slow product release, a long-chain polyprenyl pyrophosphate synthase often requires detergent or another factor for optimal activity. Our previous studies in examining the activity enhancement of Escherichia coli undecaprenyl pyrophosphate synthase have demonstrated a switch of the rate-determining step from product release to isopentenyl pyrophosphate (IPP) condensation reaction in the presence of Triton [12]. In order to understand the mechanism of enzyme activation for E. coli OPPs, a single-turnover reaction was performed and the measured IPP condensation rate (2 s(-1)) was 100 times larger than the steady-state rate (0.02 s(-1)). The high molecular weight fractions and Triton could accelerate the steady-state rate by 3-fold (0.06 s(-1)) but insufficient to cause full activation (100-fold). A burst product formation was observed in enzyme multiple turnovers indicating a slow product release.

Alkyl and Aryl Transferases↗