475682 Understanding and Controlling Protein Stability from Coarse-Grained Protein Models

Sunday, November 13, 2016
Continental 4 & 5 (Hilton San Francisco Union Square)
Marco A. Blanco, Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD

Understanding and Controlling Protein Stability from Coarse-Grained Protein Models

Marco A. Blanco

National Institute of Standards and Technology, Gaithersburg, MD 20899

Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850

Research Interests:

Protein-based therapeutics represents one of the fastest growing markets in pharmaceutical industry. The high efficacy and specificity of biotherapeutics make them valuable for targeting different type of illnesses. Nonetheless, most, if not all, proteins present a very wide range of behaviors that limit the development of commercially viable products. Small changes in the protein sequence and formulation conditions may cause conformational and physical instabilities that lead to the self-assembly of proteins (e.g., fluid phase separation, oligomerization, and irreversible aggregation). These stability concerns constitute the primary route for the formation of impurities in biotherapeutics, as well as may induce unfavorable immunologic responses in patients. The ability to accurately and unambiguously predict the behavior of proteins in solution will help control instability problems via an adequate design of proteins and selection of formulation conditions.

My research work has focused on understanding the stability of proteins in solution via simple but realistic coarse-grained computational models, which are combined with biomolecular and biophysical experiments (e.g., mutagenesis, chromatography, calorimetry, scattering) to provide both refinement and validation. By implementing advanced Monte Carlo and Molecular Dynamics techniques, these models allow one to evaluate the thermodynamic pathways by which proteins are destabilized, which might be otherwise challenging to probe due to the generally short-living nature of most of the key species in those processes. Thus, the resulting models provide powerful, physics-based tools to assess how different factors (e.g., pH, excipients, protein structure) affect those phenomena that cause instability in proteins such as phase separation, protein unfolding, and nonnative aggregation; moreover, they offer guidelines for rationally designing/selecting proteins with higher physical stability.

The Blanco laboratory will built on the use of both computational and experimental methods applied to topics within the general theme of protein stability, engineering, and self-assembly. A specific emphasis will be placed on developing new and improved theoretical models and experimental techniques to predict the conformational and solution stability of proteins and peptides, and thus to gain insights regarding how the local structure and surrounding molecular environment influence the underlying mechanisms associated to physical degradation of proteins. Such predicting methods will have direct application in fields such as biomedicine (e.g., elucidating critical stages during amyloidosis), drug discovery (e.g., rational design of high-affinity peptide-based drugs), drug development (e.g., identifying optimal formulation and manufacturing conditions for biopharmaceutics), and biomaterials (e.g., developing “smart” protein-based materials with controllable self-assembly properties). Since research in these fields encompasses various disciplines, there will be strong collaborations from both academy and pharmaceutical industry.

Teaching Interests:

In addition to my research career, I have also gained significant teaching experience. I lectured an undergraduate course at the Industrial University of Santander in Colombia about the implementation of statistical and quantum mechanical computational methods to thermodynamics and transport phenomena problems related to Chemical Engineering. I also TAed thermodynamics courses at both undergraduate and graduate level, as well as mentored undergraduate students and visiting scholars about application of molecular simulations to protein systems.

Given my background in protein science and chemical engineering, my teaching interests extend in undergraduate core chemical engineering courses that include thermodynamics, heat and mass transfer, chemical kinetics, and applied math. Furthermore, I would also like to develop and teach undergraduate- and graduate-level courses in topics such as protein engineering, statistical thermodynamics applied to chemical engineering, and computational and experimental methods for protein characterization.

Research Projects:

PhD Projects:

·      “Measuring Protein-Protein interaction via Scattering Experiments from Low to High Protein Concentrations”

·      “Evaluating the Effect of Solution Conditions and Protein Sequence on the Cluster Formation of γD-Crystallin

·      “A Novel Algorithm for Predicting Amyloidosis and Protein β-Aggregation”

·      “Solution Behavior and Aggregation Propensity of Peptide-Polyacrylic Acid Conjugates”

Supervised by Christopher J. Roberts, Department of Chemical and Biomolecular Engineering, University of Delaware.

Postdoctoral Projects:

·      “Effect of Specific Interactions on the Fluid Phase Behavior and Self-Assembly of Proteins and Nanocolloids

·      “Characterization of the Solution Structure and Phase Behavior of Monoclonal Antibodies via Coarse-Grained Models”

·      “Effect of Electrostatic Interactions on the Oligomerization and Amyloid Formation of the Cardiomyopathy-Related Protein Transthyretin”

Supervised by Vincent K. Shen and Zvi Kelman, National Institute of Standards and Technology and Institute for Bioscience and Biotechnology Research, University of Maryland.

Selected Publications:

1.     Marco A. Blanco, Erinc Sahin, Anne S. Robinson, and Christopher J. Roberts. “Coarse-grained model for colloidal protein interactions, B22, and protein cluster formation”. J. Phys. Chem. B, 117, 16013 (2013).

2.     Marco A. Blanco, Tatiana Perevozchikova, Vincenzo Martorana, Mauro Manno, and Christopher J. Roberts. “Protein-protein interactions in dilute to concentrated solutions: a-Chymotrypsinogen in acidic conditions”. J. Phys. Chem. B, 118, 5817 (2014).

3.     Bradford Paik, Marco A. Blanco, Xinqiao Jia, Christopher J. Roberts, and Kristi Kiick. “Aggregation of poly(acrylic acid)-containing elastin-mimetic copolymers”. Soft Matter, 11, 1839 (2015).

4.     Marco A. Blanco and Vincent K. Shen. “Effect of the surface charge distribution on the fluid phase behavior of charged colloids and proteins”. J. Chem. Phys. [submitted].

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