Publications (8)38.18 Total impact
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Article: Inhibition of biocatalysis in [Fe-Fe] hydrogenase by oxygen: molecular dynamics and density functional theory calculations.
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ABSTRACT: Designing O(2)-tolerant hydrogenases is a major challenge in applying [Fe-Fe]H(2)ases for H(2) production. The inhibition involves transport of oxygen through the enzyme to the H-cluster, followed by binding and subsequent deactivation of the active site. To explore the nature of the oxygen diffusion channel for the hydrogenases from Desulfovibrio desulfuricans (Dd) and Clostridium pasteurianum (Cp), empirical molecular dynamics simulations were performed. The dynamic nature of the oxygen pathways in Dd and Cp was elucidated, and insight is provided, in part, into the experimental observation on the difference of oxygen inhibition in Dd and the hydrogenase from Clostridium acetobutylicum (Ca, assumed homologous to Cp). Further, to gain an understanding of the mechanism of oxygen inhibition of the [Fe-Fe]H(2)ase, density functional theory calculations of model compounds composed of the H-cluster and proximate amino acids are reported. Confirmation of the experimentally based suppositions on inactivation by oxygen at the [2Fe](H) domain is provided, validating the model compounds used and oxidation state assumptions, further explaining the mode of damage. This unified approach provides insight into oxygen diffusion in the enzyme, followed by deactivation at the H-cluster.ACS Chemical Biology 05/2012; 7(7):1268-75. · 6.45 Impact Factor -
Article: Design parameters for tuning the type 1 Cu multicopper oxidase redox potential: insight from a combination of first principles and empirical molecular dynamics simulations.
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ABSTRACT: The redox potentials and reorganization energies of the type 1 (T1) Cu site in four multicopper oxidases were calculated by combining first principles density functional theory (QM) and QM/MM molecular dynamics (MD) simulations. The model enzymes selected included the laccase from Trametes versicolor, the laccase-like enzyme isolated from Bacillus subtilis, CueO required for copper homeostasis in Escherichia coli, and the small laccase (SLAC) from Streptomyces coelicolor. The results demonstrated good agreement with experimental data and provided insight into the parameters that influence the T1 redox potential. Effects of the immediate T1 Cu site environment, including the His(N(δ))-Cys(S)-His(N(δ)) and the axial coordinating amino acid, as well as the proximate H(N)(backbone)-S(Cys) hydrogen bond, were discerned. Furthermore, effects of the protein backbone and side-chains, as well as of the aqueous solvent, were studied by QM/MM molecular dynamics (MD) simulations, providing an understanding of influences beyond the T1 Cu coordination sphere. Suggestions were made regarding an increase of the T1 redox potential in SLAC, i.e., of Met198 and Thr232 in addition to the axial amino acid Met298. Finally, the results of this work presented a framework for understanding parameters that influence the Type 1 Cu MCO redox potential, useful for an ever-growing range of laccase-based applications.Journal of the American Chemical Society 03/2011; 133(13):4802-9. · 9.91 Impact Factor -
Article: Biophysical properties of membrane-active peptides based on micelle modeling: a case study of cell-penetrating and antimicrobial peptides.
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ABSTRACT: We investigated the molecular mechanisms of short peptides interacting with membrane-mimetic systems. Three short peptides were selected for this study: penetratin as a cell-penetrating peptide (CPP), and temporin A and KSL as antimicrobial peptides (AMP). We investigated the detailed interactions of the peptides with dodecylphosphocholine (DPC) and sodium dodecyl sulfate (SDS) micelles, and the subsequent peptide insertion based on free energy calculations by using all-atomistic molecular dynamics simulations with the united atom force field and explicit solvent models. First, we found that the free energy barrier to insertion for the three peptides is dependent on the chemical composition of the micelles. Because of the favorable electrostatic interactions between the peptides and the headgroups of lipids, the insertion barrier into an SDS micelle is less than a DPC micelle. Second, the peptides' secondary structures may play a key role in their binding and insertion ability, particularly for amphiphilic peptides such as penetratin and KSL. The secondary structures with a stronger ability to bind with and insert into micelles are the ones that account for a smaller surface area of hydrophobic core, thus offering a possible criterion for peptide design with specific functionalities.The Journal of Physical Chemistry B 10/2010; 114(43):13726-35. · 3.70 Impact Factor -
Article: Toward understanding amino acid adsorption at metallic interfaces: a density functional theory study.
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ABSTRACT: In examining adsorption of a few selected single amino acids on Au and Pd cluster models by density functional theory calculations, we have shown that specific side-chain binding affinity to the surface may occur because of a combination of effects, including charge transfer. Larger binding was calculated at the Pd interface. In addition, the interplay between amino acid solvation and adsorption at the interface was considered from first principles. This analysis serves as the first step toward gaining a more accurate understanding of specific interactions at the interface of biological-metal nanostructures than has been attempted in the past.ACS Applied Materials & Interfaces 02/2009; 1(2):388-92. · 4.53 Impact Factor -
Article: Using the constrained DFT approach in generating diabatic surfaces and off diagonal empirical valence bond terms for modeling reactions in condensed phases.
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ABSTRACT: The empirical valence bond (EVB) model provides an extremely powerful way for modeling and analyzing chemical reactions in solutions and proteins. However, this model is based on the unverified assumption that the off diagonal elements of the EVB Hamiltonian do not change significantly upon transfer of the reacting system from one phase to another. This ad hoc assumption has been rationalized by its consistency with empirically observed linear free energy relationships, as well as by other qualitative considerations. Nevertheless, this assumption has not been rigorously established. The present work explores the validity of the above EVB key assumption by a rigorous numerical approach. This is done by exploiting the ability of the frozen density functional theory (FDFT) and the constrained density functional theory (CDFT) models to generate convenient diabatic states for QM/MM treatments, and thus to examine the relationship between the diabatic and adiabatic surfaces, as well as the corresponding effective off diagonal elements. It is found that, at least for the test case of S(N)()2 reactions, the off diagonal element does not change significantly upon moving from the gas phase to solutions and thus the EVB assumption is valid and extremely useful.The Journal of Physical Chemistry B 11/2006; 110(39):19570-4. · 3.70 Impact Factor -
Article: Frozen density functional free energy simulations of redox proteins: computational studies of the reduction potential of plastocyanin and rusticyanin.
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ABSTRACT: The evaluation of reduction potentials of proteins by ab initio approaches presents a major challenge for computational chemistry. This is addressed in the present investigation by reporting detailed calculations of the reduction potentials of the blue copper proteins plastocyanin and rusticyanin using the QM/MM all-atom frozen density functional theory, FDFT, method. The relevant ab initio free energies are evaluated by using a classical reference potential. This approach appears to provide a general consistent and effective way for reproducing the configurational ensemble needed for consistent ab initio free energy calculations. The FDFT formulation allows us to treat a large part of the protein quantum mechanically by a consistently coupled QM/QM/MM embedding method while still retaining a proper configurational sampling. To establish the importance of proper configurational sampling and the need for a complete representation of the protein+solvent environment, we also consider several classical approaches. These include the semi-macroscopic PDLD/S-LRA method and classical all-atom simulations with and without a polarizable force field. The difference between the reduction potentials of the two blue copper proteins is reproduced in a reasonable way, and its origin is deduced from the different calculations. It is found that the protein permanent dipole tunes down the reduction potential for plastocyanin compared to the active site in regular water solvent, whereas in rusticyanin it is instead tuned up. This electrostatic environment, which is the major effect determining the reduction potential, is a property of the entire protein and solvent system and cannot be ascribed to any particular single interaction.Journal of the American Chemical Society 05/2003; 125(17):5025-39. · 9.91 Impact Factor -
Article: Ab Initio QM/MM Simulation with Proper Sampling: “First Principle” Calculations of the Free Energy of the Autodissociation of Water in Aqueous Solution
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ABSTRACT: Quantum mechanical calculations of activation free energies of chemical reactions in condensed phases present a major challenge for computational chemistry. On one hand, it is important to use high-level ab initio methods to obtain reliable results. On the other hand, it is essential to perform sufficient configurational sampling to obtain meaningful free energies. Although the advance of quantum mechanical/molecular mechanics (QM/MM) approaches has made this problem tractable, it still requires an enormous amount of computer time. The present work advances several strategies that allow one to perform practical ab initio QM/MM calculations of free energy profiles in solutions and proteins. The basic idea is the use of a simple reference potential for the ab initio calculations (e.g., Bentzien; et al. J. Phys. Chem. B 1998, 102, 2293). One version of this approach evaluates the free energy of transfer from the reference potential to the ab initio potential by a single step free energy perturbation (FEP) approach. A new version evaluates this free energy by the linear response approximation (LRA), which involves running trajectories on both the reference and the ab initio potentials. The performance of both approaches is examined by calculating the potential of mean force for the autodissociation reaction of water in solution. It is found that the LRA approach allows one to obtain reasonable results even in cases where the ab initio and reference potentials are significantly different. The present work also explores options for increasing the size of the quantum mechanical region. Here it is shown that the constrained DFT (CDFT) method provides a promising strategy. Finally, the general issue of modeling the autodissociation reaction by quantum mechanical approaches is briefly considered. It is pointed out that the use of the empirical valence bond (EVB) approach in the sampling process should provide a way for evaluating the elusive nonequilibrium solvation effect.12/2002; -
Article: Constraining the electron densities in DFT method as an effective way for ab initio studies of metal-catalyzed reactions.
Journal of Computational Chemistry. 01/2000; 21:1554-1561.
Top co-authors
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Institutions
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2009–2012
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Wright-Patterson Air Force Base
Dayton, OH, USA
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2003–2006
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University of Southern California
- Department of Chemistry
Los Angeles, CA, USA
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