Dataset Information

Integrated Modeling Program, Applied Chemical Theory (IMPACT).

ABSTRACT: We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high-throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function.

SUBMITTER: Banks JL

PROVIDER: S-EPMC2742605 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Integrated Modeling Program, Applied Chemical Theory (IMPACT).

Banks Jay L JL Beard Hege S HS Cao Yixiang Y Cho Art E AE Damm Wolfgang W Farid Ramy R Felts Anthony K AK Halgren Thomas A TA Mainz Daniel T DT Maple Jon R JR Murphy Robert R Philipp Dean M DM Repasky Matthew P MP Zhang Linda Y LY Berne Bruce J BJ Friesner Richard A RA Gallicchio Emilio E Levy Ronald M RM

Journal of computational chemistry 20051201 16

We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally ...[more]

PMID: 16211539

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Project description:Integrated world modeling theory (IWMT) is a synthetic theory of consciousness that uses the free energy principle and active inference (FEP-AI) framework to combine insights from integrated information theory (IIT) and global neuronal workspace theory (GNWT). Here, I first review philosophical principles and neural systems contributing to IWMT's integrative perspective. I then go on to describe predictive processing models of brains and their connections to machine learning architectures, with particular emphasis on autoencoders (perceptual and active inference), turbo-codes (establishment of shared latent spaces for multi-modal integration and inferential synergy), and graph neural networks (spatial and somatic modeling and control). Future directions for IIT and GNWT are considered by exploring ways in which modules and workspaces may be evaluated as both complexes of integrated information and arenas for iterated Bayesian model selection. Based on these considerations, I suggest novel ways in which integrated information might be estimated using concepts from probabilistic graphical models, flow networks, and game theory. Mechanistic and computational principles are also considered with respect to the ongoing debate between IIT and GNWT regarding the physical substrates of different kinds of conscious and unconscious phenomena. I further explore how these ideas might relate to the "Bayesian blur problem," or how it is that a seemingly discrete experience can be generated from probabilistic modeling, with some consideration of analogies from quantum mechanics as potentially revealing different varieties of inferential dynamics. I go on to describe potential means of addressing critiques of causal structure theories based on network unfolding, and the seeming absurdity of conscious expander graphs (without cybernetic symbol grounding). Finally, I discuss future directions for work centered on attentional selection and the evolutionary origins of consciousness as facilitated "unlimited associative learning." While not quite solving the Hard problem, this article expands on IWMT as a unifying model of consciousness and the potential future evolution of minds.

Project description:BackgroundCancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments.MethodsTissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient's epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient's primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay.ResultsOur computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model).ConclusionsThese proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.

Dataset Information

Integrated Modeling Program, Applied Chemical Theory (IMPACT).

Publications

Integrated Modeling Program, Applied Chemical Theory (IMPACT).

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