Orientation Control of Block Copolymers Using Surface Active, Phase-Preferential Additives.

Orientation control of thin film nanostructures derived from block copolymers (BCPs) are of great interest for various emerging technologies like separation membranes, nanopatterning, and energy storage. While many BCP compositions have been developed for these applications, perpendicular orientation of these BCP domains is still very challenging to achieve. Herein we report on a new, integration-friendly approach in which small amounts of a phase-preferential, surface active polymer (SAP) was used as an additive to a polycarbonate-containing BCP formulation to obtain perpendicularly oriented domains with 19 nm natural periodicity upon thermal annealing. In this work, the vertically oriented BCP domains were used to demonstrate next generation patterning applications for advanced semiconductor nodes. Furthermore, these domains were used to demonstrate pattern transfer into a hardmask layer via commonly used etch techniques and graphoepitaxy-based directed self-assembly using existing lithographic integration schemes. We believe that this novel formulation-based approach can easily be extended to other applications beyond nanopatterning.

Enabling complex nanoscale pattern customization using directed self-assembly.

Block copolymer directed self-assembly is an attractive method to fabricate highly uniform nanoscale features for various technological applications, but the dense periodicity of block copolymer features limits the complexity of the resulting patterns and their potential utility. Therefore, customizability of nanoscale patterns has been a long-standing goal for using directed self-assembly in device fabrication. Here we show that a hybrid organic/inorganic chemical pattern serves as a guiding pattern for self-assembly as well as a self-aligned mask for pattern customization through cotransfer of aligned block copolymer features and an inorganic prepattern. As informed by a phenomenological model, deliberate process engineering is implemented to maintain global alignment of block copolymer features over arbitrarily shaped, 'masking' features incorporated into the chemical patterns. These hybrid chemical patterns with embedded customization information enable deterministic, complex two-dimensional nanoscale pattern customization through directed self-assembly.

Determination of the internal morphology of nanostructures patterned by directed self assembly.

The directed self-assembly (DSA) of block copolymers (BCP) is an emerging resolution enhancement tool that can multiply or subdivide the pitch of a lithographically defined chemical or topological pattern and is a resolution enhancement candidate to augment conventional lithography for patterning sub-20 nm features. Continuing the development of this technology will require an improved understanding of the polymer physics involved as well as experimental confirmation of the simulations used to guide the design process. Both of these endeavors would be greatly facilitated by a metrology, which is capable of probing the internal morphology of a DSA film. We have developed a new measurement technique, resonant critical-dimension small-angle X-ray scattering (res-CDSAXS), to evaluate the 3D buried features inside the film. This is an X-ray scattering measurement where the sample angle is varied to probe the 3D structure of the film, while resonant soft X-rays are used to enhance the scattering contrast. By measuring the same sample with both res-CDSAXS and traditional CDSAXS (with hard X-rays), we are able to demonstrate the dramatic improvement in scattering obtained through the use of resonant soft X-rays. Analysis of the reciprocal space map constructed from the res-CDSAXS measurements allowed us to reconstruct the complex buried features in DSA BCP films. We studied a series of DSA BCP films with varying template widths, and the internal morphologies for these samples were compared to the results of single chain in mean-field simulations. The measurements revealed a range of morphologies that occur with changing template width, including results that suggest the presence of mixed morphologies composed of both whole and necking lamella. The development of res-CDSAXS will enable a better understanding of the fundamental physics behind the formation of buried features in DSA BCP films.

Expected distributions of root-mean-square positional deviations in proteins.

The atom positional root-mean-square deviation (RMSD) is a standard tool for comparing the similarity of two molecular structures. It is used to characterize the quality of biomolecular simulations, to cluster conformations, and as a reaction coordinate for conformational changes. This work presents an approximate analytic form for the expected distribution of RMSD values for a protein or polymer fluctuating about a stable native structure. The mean and maximum of the expected distribution are independent of chain length for long chains and linearly proportional to the average atom positional root-mean-square fluctuations (RMSF). To approximate the RMSD distribution for random-coil or unfolded ensembles, numerical distributions of RMSD were generated for ensembles of self-avoiding and non-self-avoiding random walks. In both cases, for all reference structures tested for chains more than three monomers long, the distributions have a maximum distant from the origin with a power-law dependence on chain length. The purely entropic nature of this result implies that care must be taken when interpreting stable high-RMSD regions of the free-energy landscape as "intermediates" or well-defined stable states.

Two-dimensional pattern formation using graphoepitaxy of PS-b-PMMA block copolymers for advanced FinFET device and circuit fabrication.

Directed self-assembly (DSA) of lamellar phase block-co-polymers (BCPs) can be used to form nanoscale line-space patterns. However, exploiting the potential of this process for circuit relevant patterning continues to be a major challenge. In this work, we propose a way to impart two-dimensional pattern information in graphoepitaxy-based lamellar phase DSA processes by utilizing the interactions of the BCP with the template pattern. The image formation mechanism is explained through the use of Monte Carlo simulations. Circuit patterns consisting of the active region of Si FinFET transistors, referred to as Si "fins", were fabricated to demonstrate the applicability of this technique to the formation of complex patterns. The quality of the Si fin features produced by this process was validated by demonstrating the first functional DSA-patterned FinFET devices with 29 nm-pitch fins.

Programmable nanoparticle ensembles via high-throughput directed self-assembly.

We present a simple and facile strategy for the directed self-assembly of nanoparticles into complex geometries using a minimal set of post guiding features patterned on a substrate. This understanding is based on extensive studies of nanoparticle self-assembly into linear, dense-packed, circular, and star-shaped ensembles when coated onto patterned substrates of predefined post arrays. We determined the conditions under which nanoparticles assemble and "connect" two adjacent post features, thereby forming the desired shapes. We demonstrate that with rational design of the post patterns to enforce the required pairwise interactions with posts, we can create arbitrary arrangements of nanoparticles-for example, to write "IBM" in a deterministic manner. This demonstration of programmable, high-throughput directed self-assembly of nanoparticles shows an alternative route to generate functional nanoparticle assemblies.

Pattern placement accuracy in block copolymer directed self-assembly based on chemical epitaxy.

The realization of viable designs for circuit patterns using the dense features formed by block copolymer directed self-assembly (DSA) will require a precise and quantitative understanding of self-assembled feature registration to guiding templates or chemical prepatterns. Here we report measurements of DSA placement error for lamellar block copolymer domains indexed to specific lines in the surface chemical prepattern for spatial frequency tripling and quadrupling. These measurements are made possible by the use of an inorganic domain-selective prepattern material that may be imaged upon polymer removal after DSA and a prepattern design incorporating a single feature serving as an in situ registration mark that is identifiable by pattern symmetry in both the prepattern and resulting self-assembled pattern. The results indicate that DSA placement error is correlated with average prepattern line width as well as prepattern pitch uniformity. Finally, the magnitude of DSA placement error anticipated for a uniform, optimized prepattern is estimated.

On the Use of Experimental Observations to Bias Simulated Ensembles.

Historically, experimental measurements have been used to bias biomolecular simulations toward structures compatible with those observations via the addition of ad hoc restraint terms. We show how the maximum entropy formalism provides a principled approach to enforce concordance with these measurements in a minimally biased way, yielding restraints that are linear functions of the target observables and specifying a straightforward scheme to determine the biasing weights. These restraints are compared with instantaneous and ensemble-averaged harmonic restraint schemes, illustrating their similarities and limitations.

Current developments in and importance of high-performance computing in drug discovery.

A number of current trends that are being adopted to reshape the field of high-performance computing exist, including multi-core systems, accelerators, and software frameworks for large-scale intrinsically parallel applications. These trends intersect with recent developments in computational chemistry to provide new capabilities for computer-aided drug discovery. Although this review focuses primarily on the application domains of molecular modeling and biomolecular simulation, these computing changes are relevant for other computationally intensive tasks, such as instrument data processing and chemoinformatics.

Comparison of computational approaches for predicting the effects of missense mutations on p53 function.

We applied our recently developed kinetic computational mutagenesis (KCM) approach [L.T. Chong, W.C. Swope, J.W. Pitera, V.S. Pande, Kinetic computational alanine scanning: application to p53 oligomerization, J. Mol. Biol. 357 (3) (2006) 1039-1049] along with the MM-GBSA approach [J. Srinivasan, T.E. Cheatham 3rd, P. Cieplak, P.A. Kollman, D.A. Case, Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate-DNA helices, J. Am. Chem. Soc. 120 (37) (1998) 9401-9409; P.A. Kollman, I. Massova, C.M. Reyes, B. Kuhn, S. Huo, L.T. Chong, M. Lee, T. Lee, Y. Duan, W. Wang, O. Donini, P. Cieplak, J. Srinivasan, D.A. Case, T.E. Cheatham 3rd., Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models, Acc. Chem. Res. 33 (12) (2000) 889-897] to evaluate the effects of all possible missense mutations on dimerization of the oligomerization domain (residues 326-355) of tumor suppressor p53. The true positive and true negative rates for KCM are comparable (within 5%) to those of MM-GBSA, although MM-GBSA is much less computationally intensive when it is applied to a single energy-minimized configuration per mutant dimer. The potential advantage of KCM is that it can be used to directly examine the kinetic effects of mutations.

Observation of noncooperative folding thermodynamics in simulations of 1BBL.

One of the predictions of the energy landscape theory of protein folding is the possibility of barrierless, "downhill" folding under certain conditions. The protein 1BBL has been proposed to fold by such a downhill mechanism, though this is a matter of some dispute. We carried out extensive replica exchange molecular dynamics simulations on 1BBL in explicit solvent to address this controversy and provide a microscopic picture of its folding thermodynamics. Our simulations show two distinct structural transitions in the folding of 1BBL. A low-temperature transition involves a disordering of the protein's tertiary structure without loss of secondary structure. A distinct, higher temperature transition involves the complete loss of secondary structure and dissolution of the hydrophobic core. In contrast, control simulations of the 1BBL homolog E3BD show a single high temperature unfolding transition. Further simulations of 1BBL at high ionic strength show a significant destabilization of helix II but not helix I, suggesting that the apparent folding cooperativity of 1BBL may be highly dependent on experimental conditions. Although our simulations cannot provide definitive evidence of downhill folding in 1BBL, they clearly show evidence of a complex, non-two-state folding process.

Soft patchy nanoparticles from solution-phase self-assembly of binary diblock copolymers.

The fabrication of highly ordered, defect-free nanostructures is a key challenge in nanotechnology. Bottom-up fabrication approaches require nanobuilding blocks of precisely defined size and shape. In this work we propose a simple approach to obtain one type of building block--soft patchy nanoparticles--suggested by a series of coarse grain molecular dynamics simulations. A binary mixture of two different diblock copolymers with a common hydrophobic block but sufficiently dissimilar hydrophilic blocks reliably self-assembles into a "patchy" spherical micelle in water, with phase separation of the two hydrophilic blocks on the surface of the micelle core. Subsequent crosslinking of the core to solidify the patchy sphere geometry should allow further hierarchical assembly. Altering the hydrophilic versus hydrophobic composition of each polymer yields a change of morphology from "patchy spheres" to "patchy cylinders". Furthermore, by controlling the interaction strength of the blocks with solvent, the patches can be selectively placed either on the outer surface or inside the core of the micelle. The number and size of the patches are found to be largely controlled by the composition of the binary copolymer mixture.

Interfacial fluctuations of block copolymers: a coarse-grain molecular dynamics simulation study.

The lamellar and cylindrical phases of block copolymers have a number of technological applications, particularly when they occur in supported thin films. One such application is block copolymer lithography, the use of these materials to subdivide or enhance submicrometer patterns defined by optical or electron beam methods. A key parameter of all lithographic methods is the line edge roughness (LER), because the electronic or optical activities of interest are sensitive to small pattern variations. While mean-field models provide a partial picture of the LER and interfacial width expected for the block interface in a diblock copolymer, these models lack chemical detail. To complement mean-field approaches, we have carried out coarse-grain molecular dynamics simulations on model poly(ethyleneoxide)-poly(ethylethylene) (PEO-PEE) lamellae, exploring the influence of chain length and hypothetical chemical modifications on the observed line edge roughness. As expected, our simulations show that increasing chi (the Flory-Huggins parameter) is the most direct route to decreased roughness, although the addition of strong specific interactions at the block interface can also produce smoother patterns.

Use of the Weighted Histogram Analysis Method for the Analysis of Simulated and Parallel Tempering Simulations.

The growing adoption of generalized-ensemble algorithms for biomolecular simulation has resulted in a resurgence in the use of the weighted histogram analysis method (WHAM) to make use of all data generated by these simulations. Unfortunately, the original presentation of WHAM by Kumar et al. is not directly applicable to data generated by these methods. WHAM was originally formulated to combine data from independent samplings of the canonical ensemble, whereas many generalized-ensemble algorithms sample from mixtures of canonical ensembles at different temperatures. Sorting configurations generated from a parallel tempering simulation by temperature obscures the temporal correlation in the data and results in an improper treatment of the statistical uncertainties used in constructing the estimate of the density of states. Here we present variants of WHAM, STWHAM and PTWHAM, derived with the same set of assumptions, that can be directly applied to several generalized ensemble algorithms, including simulated tempering, parallel tempering (better known as replica-exchange among temperatures), and replica-exchange simulated tempering. We present methods that explicitly capture the considerable temporal correlation in sequentially generated configurations using autocorrelation analysis. This allows estimation of the statistical uncertainty in WHAM estimates of expectations for the canonical ensemble. We test the method with a one-dimensional model system and then apply it to the estimation of potentials of mean force from parallel tempering simulations of the alanine dipeptide in both implicit and explicit solvent.

Absence of reptation in the high-temperature folding of the trpzip2 beta-hairpin peptide.

We have carried out extensive all atom explicit solvent simulations of the high-temperature folding and unfolding of the trpzip2 beta-hairpin peptide and examined the resulting trajectories for evidence of folding via a reptation mechanism. Over 300 microcanonical simulations of 10 ns each were initiated from a Boltzmann ensemble of conformations at 425 K. Though we observed numerous folding and unfolding events, no evidence of reptation was found. The diffusional dynamics of the peptide are orders of magnitude faster than any observed reptation-like motion. Our data suggest that the dominant mechanisms for beta-hairpin folding under these conditions are hydrophobic collapse and turn formation, and that rearrangements occur via significant expansion of the polypeptide chain.

Kinetic computational alanine scanning: application to p53 oligomerization.

We have developed a novel computational alanine scanning approach that involves analysis of ensemble unfolding kinetics at high temperature to identify residues that are critical for the stability of a given protein. This approach has been applied to dimerization of the oligomerization domain (residues 326-355) of tumor suppressor p53. As validated by experimental results, our approach has reasonable success in identifying deleterious mutations, including mutations that have been linked to cancer. We discuss a method for determining the effect of mutations on the location of the dimerization transition state.

Characterization of the TIP4P-Ew water model: vapor pressure and boiling point.

The liquid-vapor-phase equilibrium properties of the previously developed TIP4P-Ew water model have been studied using thermodynamic integration free-energy simulation techniques in the temperature range of 274-400 K. We stress that free-energy results from simulations need to be corrected in order to be compared to the experiment. This is due to the fact that the thermodynamic end states accessible through simulations correspond to fictitious substances (classical rigid liquids and classical rigid ideal gases) while experiments operate on real substances (liquids and real gases, with quantum effects). After applying analytical corrections the vapor pressure curve obtained from simulated free-energy changes is in excellent agreement with the experimental vapor pressure curve. The boiling point of TIP4P-Ew water under ambient pressure is found to be at 370.3+/-1.9 K, about 7 K higher than the boiling point of TIP4P water (363.7+/-5.1 K; from simulations that employ finite range treatment of electrostatic and Lennard-Jones interactions). This is in contrast to the approximately +15 K by which the temperature of the density maximum and the melting temperature of TIP4P-Ew are shifted relative to TIP4P, indicating that the temperature range over which the liquid phase of TIP4P-Ew is stable is narrower than that of TIP4P and resembles more that of real water. The quality of the vapor pressure results highlights the success of TIP4P-Ew in describing the energetic and entropic aspects of intermolecular interactions in liquid water.

Development of an improved four-site water model for biomolecular simulations: TIP4P-Ew.

A re-parameterization of the standard TIP4P water model for use with Ewald techniques is introduced, providing an overall global improvement in water properties relative to several popular nonpolarizable and polarizable water potentials. Using high precision simulations, and careful application of standard analytical corrections, we show that the new TIP4P-Ew potential has a density maximum at approximately 1 degrees C, and reproduces experimental bulk-densities and the enthalpy of vaporization, DeltaH(vap), from -37.5 to 127 degrees C at 1 atm with an absolute average error of less than 1%. Structural properties are in very good agreement with x-ray scattering intensities at temperatures between 0 and 77 degrees C and dynamical properties such as self-diffusion coefficient are in excellent agreement with experiment. The parameterization approach used can be easily generalized to rehabilitate any water force field using available experimental data over a range of thermodynamic points.

Heterogeneous folding of the trpzip hairpin: full atom simulation and experiment.

The beta-hairpin trpzip2 can be tuned continuously from a two-state folder to folding on a rough energy landscape without a dominant refolding barrier. At high denaturant concentration, this extremely stable peptide exhibits a single apparent "two-state" transition temperature when monitored by different spectroscopic techniques. However, under optimal folding conditions the hairpin undergoes an unusual folding process with three clusters of melting transitions ranging from 15 degrees C to 160 degrees C, as monitored by 12 different experimental and computational observables. We explain this behavior in terms of a rough free energy landscape of the unfolded peptide caused by multiple tryptophan interactions and alternative backbone conformations. The landscape is mapped out by potentials of mean force derived from replica-exchange molecular dynamics simulations. Implications for deducing cooperativity from denaturant titrations, for the origin of folding cooperativity, and for the folding of thermophilic proteins are pointed out. trpzip is an excellent small tunable model system for the glass-like folding transitions predicted by landscape theory.

Understanding folding and design: replica-exchange simulations of "Trp-cage" miniproteins.

Replica-exchange molecular dynamics simulations in implicit solvent have been carried out to study the folding thermodynamics of a designed 20-residue peptide, or "miniprotein." The simulations in this study used the amber (parm94) force field along with the generalized Born/solvent-accessible surface area implicit solvent model, and they spanned a range of temperatures from 273 to 630 K. Starting from a completely extended initial conformation, simulations of one peptide sequence sample conformations that are <1.0 A Calpha rms positional deviation from structures in the corresponding NMR ensemble. These folded states are thermodynamically stable with a simulated melting temperature of approximately 400 K, and they satisfy the majority of experimentally observed NMR restraints. Simulations of a related mutant peptide show a degenerate ensemble of states at low temperature, in agreement with experimental results.