BIOE 515 - SYSTEMS BIOLOGY AND MOLECULAR DESIGN

Instructor: Prof. Ariel Fernandez

Description

The course introduces novel concepts in biomolecular design and focuses on their impact on multi-level cellular organization. The intent of the course is to present a balanced integrative outlook at the various molecular components that determine biological function, sub-cellular organization and dysfunction. The focus is placed on the molecular aspects and design principles governing protein interactivity, cooperativity, allostery, supra-molecular organization and interactome modularity. Practical applications will be delineated, in particular those pertaining to the development of systems-based design principles to avert side effects in drug therapy.

Prerequisites

Some familiarity with protein structure and biomolecular physics at the level of Glaser *, Cantor & Schimmel ** or other standard textbooks is desirable.

(*) R. Glaser, Biophysics, Springer, Berlin, 2003.

(**) C. R. Cantor & P. R. Schimmel, Biophysical Chemistry, Vol. I, W. H. Freeman, 1987, or later editions.

Syllabus

I. The matrix of life at nanoscales or how to prevail under water

I.a. Keeping dry in water: Architectural constraints and the preservation of structural integrity in water.

I.b. The wrapping of protein structure: Hydrogen-bond microenvironments. Quasi continuous vs. discrete electrostatic models.

I.c. The stickiness of poorly wrapped structure: experimental assays.

I.d. Protein folding and the struggle for the survival of hydrogen bonds.

II. Cooperativity, function and dysfunction in molecular design

II.a. Cooperativity and water exclusion: The whole is more than the sum of the parts. Non-additive nature of cohesive forces. The many-body problems of living matter physics.

II.b. Function, packing defects and water exclusion.

II.c. Dysfunction: Inability to keep dry in water. Aberrant aggregation. Amyloidogenesis and optimum water exclusion.

II.d. Structure-based diagnosis of amyloidosis.

III. Evolution of protein function

III.a. Constraints on the molecular evolution of soluble proteins.

III.b. Tinkering with wrapping while preserving the fold: Fostering complexity, allostery and regulation while preserving the underlying function.

III.c. Molecular basis for the evolution of complexity: Getting the wrapping loose, carefully.

III.d. Towards a wrapping-based function predictor.

IV. Wrapping and large-scale proteomic organization

IV.a. Wrapping, role and centrality in the interactome.

IV.b. Evolution of network connectivity: why do the rich get richer?

IV.c. Interactome evolution and molecular disease.

V. Wrapping structure as a drug-design strategy

V.a. Targeting wrapping defects in proteins: Expanding the universe of drug targets.

V.b. Drug inhibitor as a wrapper of packing defects.

V.c. Dodging side effects by targeting nonconserved packing defects.

V.d. Sharpening the drug impact on the pharmacokinome.