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Collaboratory for Structural Nanobiology

SAMM-logo-1 In collaboration with the Imaging and Visualization Group, the SAMM Group is developing a computational methods to study the electronic properties of proteins and nanomaterial through The Collaboratory for Structural Nanobiology.

Contact Information: Dr. Igor Topol (301)846-1989
Dr. Raul Cachau (301)846-6062

Quantum Mechanical Modeling of Proteins

New semi-empirical quantum mechanical techniques can be used to model the electronic properties of proteins.

csn01 Electronic modeling can now be performed on systems with over 18,000 atoms. The extended active site of RAS is shown to the left and covalently bound inhibitors can now be examined. In contrast, standard quantum mechanical methods are limited to a few dozen atoms; the corresponding RAS active site is shown below.

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Drug design / Ultra-high resolution structure analysis

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Protonation, tautomerism and multiple error sources, including limitations in current analysis methods, conspire against the full knowledge of the conformation of molecules bound to biological targets. New procedures, combining the prowess of ultra-high resolution and ab-initio quantum mechanical methods may soon overcome these limitations and offer a new, quantitated view of the ligand binding process.

In collaboration with Dr. Marc C. Nicklaus, Head, Computer-Aided Drug Design (CADD) Group, CCR, we are performing the analysis and interpretation of strutural data at ultra-high resolution using custom tools. In particular, we are examining isoamide bonds / protein backbones and Ras inhibitors. This involves the exploration of the adaptation of QM codes to the study of electron densities at ultra-high resolution.






Protein nanocarriers modelling and 3D reconstruction

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There is a pressing need to develop new methods for the characterization of unaltered (i.e. not unstained) soft nanomaterials. Low voltage EM offers an alternative method to achieve this goal. The image processing algorithms for EM are, however, adapted to the high energy regime. We are in the process of developing new methods to produce statistical analysis of soft nanoparticles size and shape distribution and 3D reconstruction using LVEM. We are planning to use LVEM data to obtain a 3D reconstruction of soft nanoparticles and apply detailed modelling tools to study the assembling mechanism.

This project is in its initial phase and is in collaboration with Dr. Nadya I. Tarasova, Cancer and Inflammation Program, Head, Synthetic Biologics Core, CCR.







Nanoparticle/Protein Interaction

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Characterization of specific interactions between engineered nanoparticles (ENPs) and the biological matrix are a key piece in the puzzle of understanding the rules for the design of biocompatible ENPs. Cationic dendrimers exaggerated endotoxin-induced PCA, but their anionic or neutral counterparts did not; the cationic charge prompts this phenomenon, but different cationic surface chemistries do not influence it. Cationic dendrimers and endotoxin differentially affect the PCA complex. The inhibition of phosphoinositol 3 kinase by dendrimers contributes to the exaggeration of the endotoxin-induced PCA.

We are currently studying the PI3K / Dendrimer interaction by LVEM in association with Dr. Marina A.Dobrovolskaia, Section Head, Immunology, Nanotechnology Characterization Lab, Frederick National Laboratory for Cancer Research