Eric H Lee

Publications (12) View all

• Article: A Modular Fibrinogen Model that Captures the Stress-Strain Behavior of Fibrin Fibers.

  Rodney D Averett, Bryant Menn, Eric H Lee, Christine C Helms, Thomas Barker, Martin Guthold
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  ABSTRACT: We tested what to our knowledge is a new computational model for fibrin fiber mechanical behavior. The model is composed of three distinct elements: the folded fibrinogen core as seen in the crystal structure, the unstructured α-C connector, and the partially folded α-C domain. Previous studies have highlighted the importance of all three regions and how they may contribute to fibrin fiber stress-strain behavior. Yet no molecular model has been computationally tested that takes into account the individual contributions of all these regions. Constant velocity, steered molecular dynamics studies at 0.025 Å/ps were conducted on the folded fibrinogen core and the α-C domain to determine their force-displacement behavior. A wormlike chain model with a persistence length of 0.8 nm (Kuhn length = 1.6 nm) was used to model the mechanical behavior of the unfolded α-C connector. The three components were combined to calculate the total stress-strain response, which was then compared to experimental data. The results show that the three-component model successfully captures the experimentally determined stress-strain behavior of fibrin fibers. The model evinces the key contribution of the α-C domains to fibrin fiber stress-strain behavior. However, conversion of the α-helical coiled coils to β-strands, and partial unfolding of the protein, may also contribute.
  Biophysical Journal 10/2012; 103(7):1537-44. · 3.65 Impact Factor
• Article: Discovery through the computational microscope.

  Eric H Lee, Jen Hsin, Marcos Sotomayor, Gemma Comellas, Klaus Schulten
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  ABSTRACT: All-atom molecular dynamics simulations have become increasingly popular as a tool to investigate protein function and dynamics. However, researchers are concerned about the short time scales covered by simulations, the apparent impossibility to model large and integral biomolecular systems, and the actual predictive power of the molecular dynamics methodology. Here we review simulations that were in the past both hotly disputed and considered key successes, namely of proteins with mainly mechanical functions (titin, fibrinogen, ankyrin, and cadherin). The simulation work covered shows how state-of-the-art modeling alleviates some of the prior concerns and how unrefuted discoveries are made through the "computational microscope."
  Structure 10/2009; 17(10):1295-306. · 6.35 Impact Factor
• Article: Molecular modeling of swine influenza A/H1N1, Spanish H1N1, and avian H5N1 flu N1 neuraminidases bound to Tamiflu and Relenza.

  Ly Le, Eric Lee, Klaus Schulten, Thanh N Truong
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  ABSTRACT: A molecular model of the swine influenza A/H1N1 type-I neuraminidase was built using the pathogenic avian H5N1 type-I neuraminidase as a basis, due to the higher sequence identity between A/H1N1 and H5N1 (91.47%) compared to Spanish H1N1 (88.37%) neuraminidase. All-atom molecular dynamics (MD) simulations of all three neuraminidases were performed, either as apo-structures or with commercial antiviral drugs Tamiflu or Relenza separately bound; the simulations allowed for the identification of both conserved and unique drug-protein interactions across all three proteins. Specifically, conserved networks of hydrogen bonds stabilizing the drugs in the sialic acid binding site of the simulated neuraminidases are analyzed, providing insight into how disruption due to mutations may lead to increased drug resistance. In addition, a possible mechanism through which the residue 294 mutation acquires drug resistance is proposed by mapping the mutation site onto an electrostatic pathway which may play a role in controlling drug access to the binding pocket of neuraminidase, establishing a starting point for further investigations of neuraminidase drug resistance.
  PLoS currents. 01/2009; 1:RRN1015.
• Article: Molecular Basis of Drug Resistance in A/H1N1 Virus.

  Ariela Vergara-Jaque, Horacio Poblete, Eric H Lee, Klaus Schulten, Fernando González-Nilo, Christophe Chipot
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  ABSTRACT: New mutants of human influenza virus (A/H1N1) exhibit resistance to antiviral drugs. The mechanism whereby they develop insensitivity to these medications is, however, not yet completely understood. A crystallographic structure of A/H1N1 neuraminidase has been published recently. Using molecular dynamic simulations, it is now possible to characterize at the atomic level the mechanism that underlies the loss of binding affinity of the drugs. In this study, free-energy perturbation was used to evaluate the relative binding free energies of Tamiflu and Relenza with H274Y, N294S, and Y252H neuraminidase mutants. Our results demonstrate a remarkable correlation between theoretical and experimental data, which quantitatively confirms that the mutants are resistant to Tamiflu but are still strongly inhibited by Relenza. The simulations further reveal the key interactions that govern the affinity of the two drugs for each mutant. This information is envisioned to prove useful for the design of novel neuraminidase inhibitors and for the characterization of new potential mutants.
  Journal of Chemical Information and Modeling 09/2012; 52(10):2650-6. · 4.68 Impact Factor
• Article: Molecular origin of the hierarchical elasticity of titin: simulation, experiment, and theory.

  Jen Hsin, Johan Strümpfer, Eric H Lee, Klaus Schulten
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  ABSTRACT: This review uses the giant muscle protein titin as an example to showcase the capability of molecular dynamics simulations. Titin is responsible for the passive elasticity in muscle and is a chain composed of immunoglobulin (Ig)-like and fibronectin III (FN-III)-like domains, as well as PEVK segments rich in proline (P), glutamate (E), valine (V), and lysine (K). The elasticity of titin is derived in stages of extension under increasing external force: Ig domain straightening occurs first (termed tertiary structure elasticity), followed by the extension of the disordered PEVK segments. At larger extension and force, Ig domains unfold one by one (termed secondary structure elasticity). With the availability of crystal structures of single and connected Ig domains, the tertiary and secondary structure elasticity of titin was investigated through molecular dynamics simulations, unveiling the molecular origin of titin's elasticity.
  Annual Review of Biophysics 07/2010; 40:187-203. · 13.57 Impact Factor