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ABSTRACT: One well-known shortcoming of widely-used biomolecular force fields is the description of the directional dependence of hydrogen bonding (HB). Here we aim to better understand the origin of this difficulty and thus provide some guidance for further force field development. Our theoretical approaches center on a novel density-based energy decomposition analysis (DEDA) method [J. Chem. Phys., 131, 164112 (2009)], in which the frozen density energy is variationally determined through constrained search. This unique and most significant feature of DEDA enables us to find that the frozen density interaction term is the key factor in determining the HB orientation, while the sum of polarization and charge-transfer components shows very little HB directional dependence. This new insight suggests that the difficulty for current non-polarizable force fields to describe the HB directional dependence is not due to the lack of explicit polarization or charge-transfer terms. Using the DEDA results as reference, we further demonstrate that the main failure coming from the atomic point charge model can be overcome largely by introducing extra charge sites or higher order multipole moments. Among all the electrostatic models explored, the smeared charge distributed multipole model (up to quadrupole), which also takes account of charge penetration effects, gives the best agreement with the corresponding DEDA results. Meanwhile, our results indicate that the van der Waals interaction term needs to be further improved to better model directional hydrogen bonding.
Journal of Chemical Theory and Computation 12/2011; 7(12):4038-4049. · 5.22 Impact Factor
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ABSTRACT: It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylase (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity has been revealed but is not understood. Using Born-Oppenheimer ab initio QM/MM MD simulations, a state-of-the-art approach to simulating metallo-enzymes, we have found that the hydroxamic acid remains to be protonated upon its binding to HDAC8, and thus disproved the mechanistic hypothesis that the distinct zinc-hydroxamate chelation modes between two HDAC subclasses come from different protonation states of the hydroxamic acid. Instead, our simulations suggest a novel mechanism in which the chelation mode of hydroxamate with the zinc ion in HDACs is modulated by water access to the linker binding channel. This new insight into the interplay between the linker binding and the zinc chelation emphasizes its importance and gives guidance regarding linker design for the development of new class-IIa-specific HDAC inhibitors.
Journal of the American Chemical Society 04/2011; 133(16):6110-3. · 9.91 Impact Factor
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ABSTRACT: Herein we introduce a novel practical strategy to overcome the well-known challenge of modeling the divalent zinc cation in metalloproteins. The main idea is to design short-long effective functions (SLEF) to describe charge interactions between the zinc ion and all other atoms. This SLEF approach has the following desired features: (1). It is pairwise, additive and compatible with widely used atomic pair-wise force fields for modeling biomolecules; (2). It only changes interactions between the zinc ion and other atoms, and does not affect force field parameters that model other interactions in the system; (3). It is a non-bonded model that is inherently capable to describe different zinc ligands and coordination modes. By optimizing two SLEF parameters as well as zinc vdW parameters through force matching based on Born-Oppenheimer ab initio QM/MM molecular dynamics simulations, we have successfully developed the first SLEF force field (SLEF1) to describe zinc interactions. Extensive molecular dynamics simulations of seven zinc enzyme systems with different coordination ligands and distinct chelation modes (4-,5-,6-fold), including the binuclear zinc active site, yielded zinc coordination numbers and binding distances in good agreement with the corresponding crystal structures as well as ab initio QM/MM MD results. This not only demonstrates the transferability and adequacy of the new SLEF1 force field in describing a variety of zinc proteins, but also indicates that this novel SLEF approach is a promising direction to explore for improving force field description of metal ion interactions.
Journal of Chemical Theory and Computation 02/2011; 7(2):433-443. · 5.22 Impact Factor
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ABSTRACT: Histone modifications are implicated in epigenetic inheritance and are of central importance in regulating chromatin structure and gene expression. A prototype example is the trimethylation (Me3) of lysine 9 on histone 3 (H3), which is a readout by an aromatic cage of the chromodomain of heterochromatin-associated protein 1 (HP1) thereby leading to transcriptional repression and heterochromatin formation. Considering that the lysine methylation does not change the charge state of the histone tail and such aromatic-cage mediated recognition of the quaternary ammonium moiety is emerging as the most striking mechanistic commonality for the state-specific recognition of histone lysine methylation, it is of particular interest and importance to understand the physical origin regarding how the aromatic cage distinguishes between the H3K9Me3 mark and its unmethylated counterpart. Here we have simulated relative binding free energies among HP1 chromodomain-H3 tail complexes differing at position 9 of the H3 tail. Our simulated results further confirm the essential role of cation-pi interactions for the binding of a methylated H3 tail by an HP1 chromodomain but indicate that the effect from an electrostatic origin is not dominant in distinguishing between the H3K9Me3 mark and its unmethylated counterpart. Meanwhile, our calculated free energy difference between H3-tert-butyl norleucine 9 and H3-methylnorleucine 9 in their binding to the HP1 clearly reveals the importance of the charge independent interactions for the state-specific readout of histone lysine trimethylation marks.
Journal of the American Chemical Society 09/2009; 131(41):14928-31. · 9.91 Impact Factor
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ABSTRACT: In order to further improve the accuracy and applicability of combined quantum mechanical/molecular mechanical (QM/MM) methods, we have interfaced the ab initio QM method with the classical Drude oscillator polarizable MM force field (ai-QM/MM-Drude). Different coupling approaches have been employed and compared: 1. the conventional dual self-consistent-field (SCF) procedure; 2. the direct SCF scheme, in which QM densities and MM Drude positions are converged simultaneously; 3. the micro-iterative SCF scheme, in which the Drude positions of the polarizable model are fully converged during each self-consistent field (SCF) step of QM calculations; 4. the one-step-Drude-update scheme, in which the MM Drude positions are updated only once instead of fully converged during each molecular dynamics (MD) step. The last three coupling approaches are found to be efficient and can achieve the desired convergence in a similar number of QM SCF steps comparing with the corresponding QM method coupled to a non-polarizable force field. The feasibility and applicability of the implemented ai-QM/MM-Drude approach have been demonstrated by carrying out Born-Oppenheimer molecular dynamics simulations with the umbrella sampling method to determine potentials of mean force for both the methyl transfer reaction of the methyl chlorine-chlorine ion system and the glycine intra-molecular proton transfer reaction in aqueous solution. Our results indicate that the ai-QM/MM-Drude approach is very promising, which provides a better description of QM/MM interactions while can achieve quite similar computational efficiency in comparison with the corresponding conventional ab initio QM/MM method.
Journal of Chemical Theory and Computation 02/2008; 4(8):1237-1248. · 5.22 Impact Factor
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ABSTRACT: This study describes particle adhesion experiments carried out to elucidate interactions between particles in slurries used for polishing of wafers and disks. For this purpose the packed column technique was employed, which simulated chemical mechanical polishing of copper with silica and alumina, as well as of silicic oxide with ceria. The model systems consisted of uniform copper and glass beads as collectors, representing the wafers, and colloidal dispersions of silica, alumia, and silica coated with nanosize ceria, all of well-defined properties that are used as abrasives. It was shown that a strong correlation exists between deposition and detachment results of the adhesion studies and the polish rates measured using actual substrates with the same or similar slurries.
Langmuir 11/2005; 21(22):9866-72. · 4.19 Impact Factor
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ABSTRACT: Thermal oxide covered silicon wafers were polished with slurries containing (i) only nano-sized particles of ceria, monodispersed colloidal spherical silica, or hematite of different shapes, (ii) a binary mixture of the same nano-sized and uniform colloidal particles, and (iii) the same colloids coated with nano-sized ceria. The procedures for the preparation of the coated particles are described in this article. The polish rates and surface qualities were in all cases higher with mixed slurries, and even more so with coated particles. The performance of composite systems also depended on the shape of the particles, cubic ones being the most and spheres least efficient. Experimental results indicated that ceria in mixtures was responsible for the enhanced polish process, while core materials enhanced a closer contact of nano-sized particles with the wafer. In general, the polish rates were higher with the larger contact area between the abrasives and the wafer. This mechanism was further verified by polishing oxide wafers on 3-M fixed abrasive pads, which have cylindrical structures with flat surfaces.
Journal of Materials Research. 09/2003; 18(10):2323 - 2330.
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ABSTRACT: The properties of abrasive particles play a significant role in chemical mechanical polishing (CMP) of metal and dielectric films in semiconductor device manufacturing. This study investigates the effects of the particle size, shape, and hardness of abrasives on the polishing of copper and tantalum films in the presence of different slurry chemistries. Well-defined dispersions of uniform particles, including spherical silica of varying diameters, hematite of different shapes, and hematite cores coated with silica of different thicknesses, were prepared and used to polish blanket films of Cu and Ta. It was shown that the total surface area of the solids in the slurry controlled the rate of material removal by pure silica for both Cu and Ta, while the surface quality of the polished films was better when higher silica content was used. The shape or the aspect ratio of hematite particles had a minor effect on the removal rate. In contrast, when hematite particles coated with silica were employed in the polishing of Cu and Ta, the polish rate decreased with increasing thickness of the shell.
Journal of Colloid and Interface Science 06/2003; 261(1):55-64. · 3.07 Impact Factor
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ABSTRACT: The properties of abrasive particles, and their interactions with surface films to be polished, play a key role in chemical mechanical polishing (CMP). This study applies the packed column technique for the investigation of the adhesion phenomena at the particle/film interface as a function of different slurry chemistries relevant to polishing processes. Well-defined dispersions, including uniform spherical silica and silica cores coated with nanosized ceria, as well as calcined alumina were used to represent slurry abrasives, and copper or glass beads to simulate wafers or discs. It was shown that the pH and slurry flow rate had significant effects on particle attachment and removal. The results of deposition of silica particles on copper beads in the presence of various concentrations of H2O2 and of detachment from copper beads of alumina particles, loaded at different pH values, had strong correlations to the polish rates of the metal.
MRS Proceedings. 12/2002; 767.
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ABSTRACT: Thermal oxide covered silicon wafers were polished with slurries containing either nano-sized ceria (CeO2) or newly prepared uniform colloidal silica particles coated with ceria. The polish rate of the latter was significantly higher than that of pure ceria. The experiments were carried out using different concentrations of the abrasives at pH 4 and 10. Little effect on the polishing rates was noted when the conditions of the slurries were varied, which was explained by the compensation of two opposite polishing mechanisms.
Journal of Materials Research. 09/2002; 17(10):2744 - 2749.
