William A. Goddard, III - US grants

This research project is directed in two major thrust areas (i) processing of metal alloys and (ii) processing of semiconductor materials. A component connecting both of these areas is simulation and theory work aimed at predicting materials properties. The metal processing research employs ion beam mixing, shock consolidation, mechanical alloying, and synthesis of layered and metastable materials. The semiconductor processing research employs epitaxial growth on Si and GaAs, ion implantation, nucleation and growth on new phases such as amorphous carbon. The use of sophisticated electron microscopy apparatus is central to the research projects. Better understanding of the influence of interfaces, surfaces and grain boundaries on materials properties is a primary goal of this reserach.

technology /technique development; proteins; computers; biomedical resource; biological products;

DESCRIPTION (Adapted from applicant's description): Neonatal bacterial meningitis caused by E.coli, results in a fatality rate ranging from 15% to 40%, and approximately 50% of the survivors sustain neurological sequelae. The mechanism involved in the invasion of E.coli into the central nervous system to cause meningitis is not known. It has been shown that the successful traversal of E.coli across the blood brain barrier requires the interaction of the outer membrane protein A (OmpA) on the E.coli with the host BMEC which constitutes the blood brain barrier. The objective of this proposal is to derive structure-based binding criteria for the development of effective inhibitors for the binding of the E.coli to the BMEC via OmpA. The investigators propose to use atomistic simulations to characterize the specific determinants for binding of N-acetyl glucosamine dimer(which are present on the glycoproteins in BMEC ) and its derivatives to the OmpA of E.coli. They would also determine why OmpA binds specifically to the BMEC and not to the systemic endothelial cells. The results of this proposal would provide criteria for effective binding useful in the design and testing of inhibitors for OmpA binding to BMEC.

This award was made on a collaborative proposal submitted to the Division of Materials Research under the Information Technology Research solicitation NSF-04-012. The Division of Materials Research, the Chemistry Division, and the Division of Computing and Communications Foundations fund this award. The other proposals in this multidisciplinary collaborative are 0427188 and 0427540 and involve investigators at Caltech and Purdue. Research activities covered by this award fall under the National Priority Area, "Advances in Science and Engineering," and the Technical Focus Area, "Innovation in Computational Modeling or Simulation in Research." This award supports computational research and algorithm development with the aim of developing new modeling tools for materials failure and with the further aim of applying these tools to advance the understanding of stress corrosion cracking. This award also supports related educational activities some of which involve underrepresented groups.

The PIs aim to develop a scalable parallel and distributed computational framework consisting of methods, algorithms, and integrated data handling and visualization tools for: 1) an accurate quantum mechanical-level (QM) description; 2) reactive force fields (ReaxFF) to describe chemical reactions and polarization; 3) molecular dynamics (MD) simulations to extract atomistic mechanisms of SCC; 4) accelerated dynamics for long-time behavior to obtain parameters directly comparable to experiments; and 5) "atomistically informed" continuum models to reach macroscopic length and time scales. Automated model transitioning by novel techniques will be employed to embed higher fidelity simulations inside coarser simulations only when and where they are required, while controlled error propagation will ensure the overall accuracy of the results. The PIs plan to use this hierarchical multiscale computational framework to study stress corrosion cracking (SCC) of aluminum, iron, and nickel-aluminum superalloys in gaseous and aqueous environments. These materials are used widely in industrial applications and their performance and lifetime are often severely limited by stress corrosion in environments containing oxygen and water. Simulations will be used to extract an atomic-level understanding of the basic mechanisms underlying SCC. The PIs plan to investigate SCC inhibition by ceramic coatings (e.g., alumina and silicon carbide), self-assembled monolayers (e.g., oleic imidazolines), and by microorganisms (e.g., Shewanella oneidensis strain MR-1).

The PIs will deliver software tools having broad applicability across scientific disciplines and industry. This award supports annual computational science workshops for undergraduate students and faculty mentors from underrepresented groups. Workshops will be organized to foster close interactions between underrepresented minority graduate students at US institutions and postdoctoral level counterparts from Latin American institutions. Undergraduate students will be involved in the research through summer research experiences; at least half are expected to be from underrepresented groups. The PIs will also assist minority institutions in developing computational science curricula, and mentor early-career faculty from minority institutions and EPSCoR states.

This award also supports education. Elements of the PIs' education program include: 1) a unique graduate course jointly taught by USC and Caltech faculty emphasizing hands-on experience in hierarchical multiscale material simulations; 2) a dual-degree program at USC offering graduate students the opportunity to obtain a PhD in the physical sciences or engineering and an MS in computer science with specialization in high performance computing and simulations; and 3) summer research experiences for undergraduate students involving a total immersion course in computational science followed by research in simulation, parallel algorithms and visualization.
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This award was made on a collaborative proposal submitted to the Division of Materials Research under the Information Technology Research solicitation NSF-04-012. The Division of Materials Research, the Chemistry Division, and the Division of Computing and Communications Foundations fund this award. The other proposals in this multidisciplinary collaborative are 0427177 and 0427540 and involve investigators at Caltech and Purdue. Research activities covered by this award fall under the National Priority Area, "Advances in Science and Engineering," and the Technical Focus Area, "Innovation in Computational Modeling or Simulation in Research." This award supports computational research and algorithm development with the aim of developing new modeling tools for materials failure and with the further aim of applying these tools to advance the understanding of stress corrosion cracking. This award also supports related educational activities some of which involve underrepresented groups.

Stress corrosion cracking (SCC) is a complex technological and economic problem involving premature and catastrophic failure of materials due to an insidious combination of mechanical stresses and chemically aggressive environments. Safe and reliable operation of structural systems are endangered by uncertainties in SCC, the reduction of which could have enormous economic impact. The PIs plan to develop computational tools that contain essential physics across a wide range of length and time scales to achieve an atomic-level mechanistic understanding of SCC. Because of the large number of atoms and complex physical and chemical processes, these tools will be able to manage distributed computing resources and focus them on SCC simulation.

The PIs plan to use these tools to study SCC of aluminum, iron, and nickel-aluminum superalloys in gaseous and aqueous environments. These materials are used widely in industrial applications and their performance and lifetime are often severely limited by stress corrosion in environments containing oxygen and water. Simulations will be used to understand the basic mechanisms underlying SCC. The PIs plan to investigate how various coatings and microorganisms inhibit SSC.

This award also supports education. Elements of the PIs' education program include: 1) a graduate course jointly taught by USC and Caltech faculty emphasizing hands-on experience in hierarchical multiscale material simulations; 2) a dual-degree program at USC offering graduate students the opportunity to obtain a PhD in the physical sciences or engineering and an MS in computer science with specialization in high performance computing and simulations; and 3) summer research experiences for undergraduate students.

The PIs will deliver software tools having broad applicability across scientific disciplines and industry. This award supports annual computational science workshops for undergraduate students and faculty mentors from underrepresented groups. Workshops will be organized to foster close interactions between underrepresented minority graduate students at US institutions and postdoctoral level counterparts from Latin American institutions. Undergraduate students from underrepresented groups will be involved in the research. In addition, the PIs will assist minority institutions in developing computational science curricula, and mentor early-career faculty from minority institutions and EPSCoR states.
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Project Summary In 2004,the 90 nm node for CMOS-based Si integrated circuits was commercialized.90
nm refers to the 'half-pitch ' between the most closely spaced metal lines the actual pitch of those lines is 180 nm..Assuming that the current scaling trends continue,technology nodes within the 10-15 nm range would be commercialized around the timeframe 2020 or so.It has previously not been possible to even explore circuitry at these dimensions,since no patterning method for creating such ultra-high density semiconductor circuitry existed.However,the SNAP (superlattice nanowire pattern transfer)method has been recently demonstrated as capable of producing relatively large scale,highly conducting Si nanowire circuits at these dimensions.
The work proposed herewill utilize these circuits,and will focus on addressing some of the most fundamental,chemical,and materials issues that are associated with scaling semiconductor computational circuitry to near molecular dimensions.The intellectual merit of this work will be to establish whether or not it is even possible to scale CMOS circuitry to such extremes.The broader impact is that,regardless of what computational paradigm follows the current one,a high levelof manufacturing perfection at the atomic scale is likely to be necessary.
The work described in this proposal will lay much of the foundation for achieving such perfection.
In the spirit of the RFA,certain approaches described here require manufacturing at a near atomic level of
control,although parallel fabrication approaches for achieving such perfection are proposed,rather than atom by atom assembly approaches.Also,in the spirit of the RFA,architectural approaches for novel omputational schemes,such as those that can take advantage of highly regular circuit structures,or that can bridge length scales from the nano-scale of the logic circuits to the sub-micron scale of standard lithography,will be exploited.
In fabricating and utilizing ultra-dense silicon circuitry,several chemical and materials issues become im-
portant.For example, as Si wire widths are reduced to a few nm,the role that surface states play in the conductivity characteristics of the nanowires becomes increasingly important.Since oxide passivation of Si reduces the mobility of charge carriers near the surface,we want to replace the oxide with an atomically perfect (and very thin)surface passivant.We propose to explore the use of methyl termination of Si(111)for applications to these circuits,an alternative that has been demonstrated to be air-stable with atomically complete passivation that dramatically reduces the surface charge carrier recombination velocities.
Silicon conductors with a thin,high-k gate dielectrics and metal gate electrodes are envisioned to become
important by decade 's end.Equally important for more extreme scaling,will be low-k dielectrics that serve to electronically isolate one nanowire from its nearest neighbor,so that the field-gating can be localized to individual nanowires within a high density logic circuit.These issues will be addressed by combining theoretical modeling to determine effective dielectric constants of ultra-thin materials and molecular films with experimental studies incorporating atomic-layer deposition of high-k gate dielectrics (i.e.HfO2)coupled with the incorporating low-k dielectrics for separating the Si nanowire conductors.
Finally,ultra-high density patterning methods will likely be limited in terms of the physical complexity
achievable in a circuit design.This requires the incorporation of novel approaches for bridging the length scales between the sub-micron world of lithography and the nanometer world of ultra-high density circuits.It also requires novel architectural concepts to take advantage of highly-or quasi-regular patterning methods.Architectural approaches that solve these issues will provide a driver for much of the fundamental science described herein.

[unreadable] DESCRIPTION (provided by applicant): The dopaminergic system plays an important role in the control of a variety of functions including motor activity, cognition, emotion, positive reinforcement, pleasure and reward, food intake, and endocrine regulation. It is implicated in such diseases as schizophrenia (excess of dopamine), Parkinson's disease (lack of dopamine), drug abuse, and alcoholism, all of which involve imbalances in the level of dopamine. Five subtypes of dopamine receptors mediate the function and the level of the dopamine neurotransmitter. Dopamine receptor antagonists have been developed to block hallucinations and delusions that occur in schizophrenic patients, whereas dopamine receptor agonists are effective in alleviating the hypokinesia of Parkinson's disease. However, blocking dopamine receptors can induce side effects similar to those resulting from dopamine depletion, and high doses of dopamine agonists can cause psychoses. Thus it is important to develop agonists and antagonists that are selective for a particular receptor subtype. Because of the similarity in the binding sites for these receptors, developing such subtype specific receptors has been too slow, partly because of the lack of 3D structures for any dopamine receptor or any homologous receptor Dopamine receptors belong to the large G-Protein Coupled Receptor (GPCR) family of seven helical transmembrane proteins. It has not yet been possible to obtain experimental 3D structures for these receptors, but we have developed the MembStruk computational strategy to predict the 3D structure sufficiently accurately that the HierDock computational strategy can predict the binding sites for small molecules. Indeed preliminary studies for bovine rhodopsin, human D2 dopamine receptor, p2-adrenergic receptor, and olfactory receptors are all consistent with available experimental results. We find that the binding site of dopamine in human D2 receptor, and epinephrine in (32 adrenergic receptor is in excellent agreement with the mutation experimental results. Here we propose a rigorous validation of these computational methods by predicting the structure and ligand binding sites of various agonists to both D1 and D5 subtypes of dopamine receptor. The predictions made by computations will be validated and tested by experiments. This exploratory collaborative study between experiments and theory will be used to validate the ab initio computational methods and will lay the basis for testing the feasibility of using these first principles methods for structure-based design of anti-Parkinsonian and anti-schizophrenic drugs, specific to each dopamine receptor. Moreover these computational methods developed and refined in this project can be applied for other more complex GPCR systems like the lipid and peptide receptors. [unreadable] [unreadable]

This research will develop a strategy for using first principles theory and computation to determine the atomistic details of polymer hydrogel double network structures applicable in the development of scaffold-supported cell therapies to promote cartilage regeneration. Recent advances in first-principles-based molecular simulations that allow the description of systems with 1,000s-millions of atoms with chemical and structural detail at the Materials and Processing Simulation Center in the California Institute of Technology will enable the essential framework to:
1) simulate the critical nano bio-mechanical properties of gel polymer networks, including mechanoregulation, and
2) develop an increased understanding of fundamental mechanisms that regulate in-vivo performance for the development of new/enhanced materials.
This work will validate the strategy on prototypical systems and set the stage for important applications in Tissue Engineering.
This research is critical to improve our understanding of, and to enhance our ability to emulate the, nano-mechanical properties of natural cartilage. Cartilage has a limited self-repair capacity and traditional therapies for musculoskeletal conditions involving cartilaginous tissue have relied on surgical procedures for full joint replacements when local repair/replacement is not possible; these methods have proven to be ineffective in the long-term. Musculoskeletal conditions remain as one of the major health concerns in the United States imposing a huge economic load on individual/public health care costs, leading to prolonged disabilities and decreased productivity of our workforce, with further socio-economic impact. Engineering/Science students will be recruited for this research and findings incorporated into a course on "Atomistic Simulation of Materials" at Caltech.

With this award from the Major Research Instrumentation (MRI) program and the Chemistry Division, Professor Thomas F. Miller and colleagues John F. Brady, William A. Goddard, Zhen-Gang Wang and Niles A. Pierce from the California Institute of Technology will acquire a computer cluster with graphical processing units. The proposal will enhance research in a variety of areas characterized as soft matter behavior/simulations. The projects include investigations aimed at the rational design of nucleic acid, protein and enzyme systems, conformational dynamics of proteins and molecular motors, enzyme-catalyzed electron-transfer and hydrogen-transfer dynamics, trans-membrane signaling and transport processes, the nucleation of membrane adhesion, protein secretion across a cellular membrane, the formation of gels, the dynamics of ring-polymer mixtures, and polymer-based tissue engineering.

A computer cluster is a group of linked processors that work in concert to achieve vastly more computational power that individual computers. These are employed to investigate complex problems using computational methods based on theoretical models and programs. Such calculations, often used in conjunction with experimental data, allow chemists and biochemists to better understand many types of complex chemical and biological phenomenon. This resource will be used by students and faculty to develop the use of computer clusters based on graphical processing units (GPUs) rather than CPUs. This approach can speed up calculations and simulations enabling larger, more complex systems to be investigated.

DESCRIPTION (provided by applicant): Escherichia coli K1 is the most common cause of meningitis in neonates. Ineffectiveness of antibiotic therapy over the last few decades and the emergence of antibiotic resistant E. coli strains imply that there is a great unmet need for new methods of treatment and prevention. Incomplete understanding of the mechanisms involved at every step of pathogenesis is attributed to this poor outcome. For example, the mechanisms by which E. coli K1 enters the human brain microvascular endothelial cells (HBMEC) that constitute the BBB and disrupts tight junctions (TJs) are poorly understood. We have established that outer membrane protein A (OmpA) of E. coli interacts with endothelial cell gp96 (Ecgp);a receptor specifically expressed on HBMEC, to invade and disrupt the TJs. The importance of OmpA-Ecgp interaction is further supported by our findings that 1) E. coli strains that either lack OmpA or express non-functional OmpA do not induce meningitis in a newborn mouse or rat model and 2) Mice in which Ecgp expression was suppressed were resistant to E. coli infection. Intriguingly, OmpA interaction with Ecgp triggers the production of nitric oxide (NO) due to iNOS activation and thereby enhances the expression of the receptor to allow the bacteria to invade more efficiently. In agreement, iNOS-/- mice are resistant to E. coli infection and also administration of an iNOS specific inhibitor, aminoguanidine (AG), during high-grade bacteremia prevented the occurrence of meningitis. Novel computer modeling methods were utilized to study the interaction of OmpA and Ecgp and to identify small molecule inhibitors that prevent the E. coli invasion of HBMEC. Three small molecules exhibited more than 80% inhibition of E. coli invasion in HBMEC both in vitro and in vivo. Our studies have also revealed that Ecgp interaction with Robo4 at the HBMEC membrane increases upon infection with E. coli. Further, a GTPase activating protein, IQGAP1, which binds both actin and b-catenin, appears to play a role in the invasion process. IQGAP1 is a client protein for Stat3, which was shown to be associated with Ecgp, indicating that IQGAP1 might be relaying Ecgp mediated signals to induce E. coli invasion. Thus, our hypothesis is that the interaction of OmpA and Ecgp is fundamental to initiate signaling events that induce E. coli invasion and increased permeability of the BBB. In Aim 1, we propose to define the binding domains of Ecgp that orchestrate the interaction of Ecgp/Robo4 with OmpA. Next, to understand whether Ecgp interaction with Robo4 contributes to signaling events to induce NO production and thereby modulating IQGAP1 association with b-CAT to dislodge it from TJs will be tested in Aim 2. Then, in Aim 3 we will modify the antagonists for higher inhibition efficiency and couple them to nanoparticles, which will carry a load of iNOS inhibitors to deliver to brain to prevent E. coli induced meningitis in newborn rats. Translational medicine is the outcome of this application in which studies of basic biology and applied technology to develop new strategies of prevention will be integrated. PUBLIC HEALTH RELEVANCE: Ineffectiveness of antibiotic therapy over the last few decades and the emergence of multidrug resistant strains make the neonatal meningitis due to E. coli K1 a serious health problem;and imply that there is a great unmet need for new methods of treatment and prevention. Our studies have demonstrated that the interaction of OmpA and endothelial cell gp96 (Ecgp) is fundamental to initiate signaling events that induce E. coli invasion and increased permeability of the blood-brain barrier (BBB). In this application, we will dissect the structural features of Ecgp that promote signaling events necessary for the invasion process and to breach the BBB permeability, which information will be used to develop Ecgp antagonists to couple to nanoparticles for targeted delivery to brain for preventing E. coli meningitis in newborn animals.

With this award from the Chemical Catalysis Program of the Chemistry Division, Professor William A. Goddard and colleague Robert Nielsen from the Departments of Chemistry and Chemical Engineering at the California Institute of Technology will develop and apply reactive force field (ReaxFF), through Monte Carlo (MC) and molecular dynamics (MD) simulations, to determine the in situ atomic scale structure of catalyst surfaces and heterogeneous interfaces in coordination with quantum mechanical (QM) studies of reactivity. The multiparadigm ReaxFF/MC/MD framework will be used to resolve the integral-occupation supercell structures of occupationally disordered multimetal oxides responsible for propane and propene ammoxidation. Most prominent among these are MoVNbTeO catalysts for ammoxidation of propene to acrylonitrile. Combining high temperature reactive dynamics trajectories with quantum-mechanical studies of key intermediates and transition states, the metallic elements involved in rate- and selectivity determining CH activation and carbon-heteroatom bond-forming steps will be identified. Separately, the chemical mechanism by which vanadyl pyrophosphate ((VO)2P2O7) stores oxygen atoms at its surface for use in the 14-electron oxidation of butane to maleic anhydride will be determined by simulating the annealing and calcination of large unit cell models of the vanadyl pyrophosphate and other high oxidation state V/P/O phases. New heterogeneous multimetallic catalysts for hydrocarbon functionalization will be posited through the optimal combination of the CH activation, radical trapping, ammonia activation and oxygen activation functions of existing catalysts. This computational framework has been validated on simpler bimetallic oxides, and will continue to be optimized. Developmental work will focus on (1) streamlining the fitting of force-field parameters for new combinations of elements against QM training sets and (2) extending the MC application of ReaxFF to grand canonical implementations.

Interfacial phenomena in catalysis and applications necessary for sustainable energy consumption occur at a regime too large for mature quantum mechanics-based simulations to play a predictive role: passivation and band tuning at semiconductor surfaces, grain boundaries in layered thermoelectric materials, semiconductor-metal and semiconductor organometallic solvent interfaces which facilitate charge transfer between photosensitive and catalytic components in photosynthetic or photovoltaic devices. The broader scientific impact of developing the ReaxFF/MC/MD approach to classical but reactive molecular dynamics simulations will be a tool for addressing a limiting factor in many heterogeneous catalysis and interfacial science applications: determining atomic-scale structures under operating conditions. Multimetal oxide catalysts are used to produce the commodity chemicals acrolein and acrylonitrile from propene, and even small improvements in catalytic performance (i.e., selectivity and activity) will have a substantial effect on energy consumption and yield. The economic impact of replacing propene with propane cannot be overstated. Since propene is generated from propane with an approximate cost of 10 ¢/lb, elimination of this step has the potential to save the US chemical industry several hundred million dollars per year. In addition, each quarter of Prof. Goddard's year long class is informed by progress in the group's current research. Applications which illustrate specific kinds of atomic interactions are discussed in the quarter of lectures in chemical physics; new and established computational techniques are taught in the quarter of lectures on methods; methods and software developed through the group's research are applied by students from experimental groups in the quarter of hands-on project work in students' respective fields.

The research objective of this project is to develop DNA nanostructures that can self-assemble into larger one dimensional and two dimensional arrays capable of programmable self-replication and programmable origami folding into complex, predictable three dimensional shapes. The resulting nanostructured origami will organize embedded non-DNA components into intricate geometries that enable new material properties and device functionalities. This project brings together a team of leading experts and practitioners from the sciences, mathematics, and sculptural arts who will draw upon their diverse expertise and inspirations to tackle collaboratively the technical challenges from both theoretical and experimental perspectives. The project is also educating a new generation of scientists and students capable of developing new paradigms for functional nanomaterial and communicating the excitement and possibilities of these results to the public at large.

If successful, the benefits of this project will be to enable the easy and economical self-replication of complex three dimensional nanostructures using mass produced components, through our progress in meeting the challenges of preparing the difficult original template structures. Self-replication will also facilitate the evolution of better materials or devices from generation to generation. Thus, in the long term, a research group may develop a DNA-organized optical metamaterial, and then immediately obtain large quantities of the prototype by introducing the initial template into a vat of components routinely ordered from a general foundry; similarly, a medical team may be able to create a complex immunotherapeutic vaccine by evolving a DNA nanostructure which displays a variety of antigens and adjuvants in some optimal, but initially unknown, three dimensional configuration; in the same vein, an environmental cleanup crew may be able to produce rapidly large quantities of a nanodevice tailored for breaking down different water borne pollutants via the solar powered activity of multiple enzymes clustered around light harvesting complexes. Thus, the capabilities we are developing will facilitate previously unimagined methodologies in the production of useful and valuable new materials.

This project is jointly sponsored by the National Science Foundation and the US Air Force Office of Scientific Research.