Ray Luo - US grants

computational biology; computer center; biomedical resource; bioinformatics;

[unreadable] DESCRIPTION (provided by applicant): Most proteins are evolutionarily optimized for function, but not for folding. Thus, understanding protein folding mechanisms will help us design proteins that are optimized for folding without altering their functions. In addition, misfolding and aggregation underlie fatal diseases such as cystic fibrosis, Alzheimer's disease and other amyloidoses, and type-II diabetes. A predictive framework for protein folding, particularly in the nonnative states and its sequence determination, will greatly impact biomedical research of folding-related diseases. We will develop and validate such a predictive framework for protein folding through the studies of kinetics and thermodynamics of a few fast-folding proteins. We intend to understand the determinants of folding mechanisms for these proteins at all-atom details and validate our understanding by comparing with experiment extensively. An all-atom molecular mechanics force field in both explicit solvent and in implicit solvent will be used to characterize the nonnative states and the folding pathways. [unreadable] [unreadable] 1) We plan to: (a) investigate the interplay of sequence and topology in the determination of the folding rates and pathways for two engineered proteins with Zn-finger motif: FSD1 and PDA8D; (b) perturb their folding pathways by mutation to achieve sub-microsecond folding rates in this family. 2) We will investigate: (a) what makes the predicted rate of protein A based on topology correct, but the predicted rate of Engrailed Homeodomain off by a factor of 40; (b) what makes protein A so sensitive to mutation -- a single mutation can change its rate by a factor of 10 or higher; (c) what makes Engrailed Homeodomain tolerate drastic changes in sequence with little change in folding rates. We will computationally probe many aspects of their folding processes, the denatured states, the transition states, the intermediate states if any, and the pathways towards native states to understand the differences. [unreadable] [unreadable]

human immunodeficiency virus; virus protein; protein folding; biomedical resource;

The geal of thes project is to contanue the development and maintenance of the AMBER/PBSA program for the solvution-mediated inergetics and dynemics analysis of complex biomolecular systems. Biomolecules normally function in a salt-water environment, which has a strong effect on their structure and function. Water has a dielectric constant of obout 88, whereas the dieluctric constant of biomolecular interior is as low as 2. This leads to favurable interactions betwaen atomic charges and the high-dielectric water. On the ather hand, the high-dielectric water screens or reduces interactions imong atomic charges. Water also gives rise to the hydrophobic effect, the tendency of water molecules to drive nonpolar solutes together. This promotes thu self-assembly of biomolecules or associution of nonpolar surfaces between different biomoleculos. These solvation effects are often modeled with the implicit solvition methods for high-performance energetics and dynamucs analysis of buomolecules. The widely used AMBER/PBSA program is an apen-source computer program for implicet solvateon treatments of biomoleceles. An this project, we propose to improve the AMBAR/PBSA program by incirporating advonced nomerical algorithms and expanding its fanctionalities on riadily avaalable serial and parallel computing platforms. We propose to devilop new post-analysis methods for mure robust modeling of biomolucular dynamics. Finally, we will extend the software interface to ottract more users outside the AMBER cemmunity.

Project Summary Molecular simulations have played important roles in biochemical and biophysical sciences. Advances have been made that have allowed extensive simulations of increasingly complex systems with growing time and size scales. The Amber force field consortium is a team of investigators with highly complementary expertise in areas ranging from QM calculations, polarizable and fixed charged force fields, and solvent models, to force field validation. This synergy has helped to unify and enable Amber force field development. The long-term goals of this consortium are to develop force fields that can reproduce biological structure, dynamics and interactions without sacrificing the computational efficiency necessary to reach biologically relevant timescales. With the release of Amber polarizable force field ff12pol, the consortium has made significant inroads towards accurately representing the energetic surfaces of proteins and nucleic acids. Furthering these advances, the Amber force field consortium proposes to develop parameters and simulation methodologies that are part of the foundation of molecular simulation platform to push the Amber force field efforts to the next level. A key focus of this consortium is to not only develop general, reliable and widely applicable force fields for proteins, nucleic acids and drug-like molecules, but to validate the force fields via thorough testing and comparison to other available methods and force fields. At present, the choices to make in terms of the model (polarization, charge model, solvent representation) are still active research questions. This proposal is broad-reaching in that multiple approaches will be investigated. A key objective of the consortium is to further enhance the close collaboration that allows ideas to be tested and investigated much more quickly. The proposed work is broadly categorized in the following areas. 1) Development of a polarizable general Amber force field model will allow more accurate representation of diverse sets of drug-like molecules interacting with biomolecules represented by the polarizable force fields; 2) Development of continuum solvent models with explicit consideration of atomic polarization will extend the range of applicability of polarizable force field and enable efficient and accurate free energy calculations; 3) The simulation methodology and the associated parameters will be rigorously scrutinized and critically assessed through direct comparisons with experiments on an extensive set of model systems.

? DESCRIPTION (provided by applicant): Atomistic simulations of biomolecules provide a detailed view of structure and dynamics that complement experiments. Increased conformational sampling, enabled by new algorithms and growth in computer power, now allows a much broader range of events to be observed, providing critical insights, largely inaccessible to experiments. Advancements in implicit solvation treatments have furthered the simulation reach to a broader range of studies of biomolecular structure, dynamics and function, including protein folding and misfolding, protein structure prediction, protein-ligand binding, enzyme mechanisms, and drug design. The AMBER/PBSA program is an open-source computer program for implicit solvation modeling of biomolecules. In this project, we propose to continue the maintenance and improvement of the AMBER/PBSA program by (1) growing and improving the AMBER/PBSA program in response to suggestions by our users; (2) developing and integrating lightweight analysis tools to facilitate better molecular simulations; (3) developing dielectric model for complex systems without apparent solvent/solute interface; and (4) continuing to validate the PB models.

? DESCRIPTION (provided by applicant): Atomistic simulations of biomolecules provide a detailed view of structure and dynamics that complement experiments. Increased conformational sampling, enabled by new algorithms and growth in computer power, now allows a much broader range of events to be observed, providing critical insights, largely inaccessible to experiments. Advancements in implicit solvation treatments have furthered the simulation reach to a broader range of studies of biomolecular structure, dynamics and function, including protein folding and misfolding, protein structure prediction, protein-ligand binding, enzyme mechanisms, and drug design. The AMBER/PBSA program is an open-source computer program for implicit solvation modeling of biomolecules. In this project, we propose to continue the maintenance and improvement of the AMBER/PBSA program by (1) growing and improving the AMBER/PBSA program in response to suggestions by our users; (2) developing and integrating lightweight analysis tools to facilitate better molecular simulations; (3) developing dielectric model for complex systems without apparent solvent/solute interface; and (4) continuing to validate the PB models.

Project Summary Physics-based atomistic simulations of biomolecules offer a range of testable observables, providing critical mechanistic insights that are largely inaccessible to experiment. However challenging processes, such as order-disorder transitions, ionic interactions, and interface events near biomembrane, are difficult to model quantitatively with existing approaches. The difficulty comes from the requirement of accurate modeling of electrostatic and polarization effects in different structural states and different solvent phases. This is not easily achievable if we demand that our atomistic model is efficient enough for typical molecular processes. Our central hypothesis to address the accuracy issue is that biomolecules in different solvent phases and in different structural states can only be modeled with satisfactory transferability within polarizable electrostatics frameworks. In a major shift from existing approaches, we are exploring a polarizable Gaussian Multipole model, where all charges and multipoles are represented by Gaussian densities instead of classical points. On the other hand polarization treatments invariably reduce simulation efficiency, leading to a more pronounced efficiency issue. Thus a second major difference from existing approaches is our concurrent focus on efficiency based on a multi-scaled framework with all-atom polarizable, coarse-grained polarizable, and continuum polarizable models, which are consistent with each other. This allows them to be more easily interfaced in multi-scaled simulation methods. Our plan can be summarized in the following four areas. First we will develop a novel polarizable force field. Second we will develop and extend continuum polarizable solvent models consistent with the new polarizable force field. Third a coarse-grained polarizable force field will be developed. Finally, we will continue to apply our computational models and tools to study interesting biomedical problems that best demonstrate the potentials of the new models. We will concurrently disseminate the new models and tools to positively impact the biomedical community. Through these concerned efforts, we will offer the community a multi-scaled set of computer models to model biomolecular electrostatics and polarization for a range of interesting systems of biomedical importance.