Integrating Innate Immunity into a Global “Systems” Context: The Complement Paradigm Shift - Systems Biology: Networks, Models, and Applications - page 171

It is our conviction that biomedical discovery will be spearheaded in
the next decade by combinatorial and cross-disciplinary approaches
(such as those outlined in the present chapter) that will address basic
biological networks in a global and integrated manner. Furthermore,
the mining of biomolecular and textual databases will essentially com-
plement these experimental strategies and enable scientists to form the
integrative context for hypothesis-driven scientific discovery.
STUDIES ON PROTEIN-PROTEIN INTERACTIONS OF
COMPLEMENT COMPONENTS
Biophysical and Computational Studies of Protein-Protein
Interactions in the Complement System
Biomolecular interactions (DNA-protein or protein-protein) are the
core component of complex biological networks and define at a molec-
ular level the nature of diverse cellular regulatory networks.
Computer-assisted modeling is a means by which such complex
interactions can be simulated, optimized, or even predicted in a quan-
titative and dynamic manner. The use of mathematical algorithms
coupled to the power of supercomputing is integral to elucidating
structure/function relations within these complex interactions.
Computational studies greatly rely on the fine resolution of three-
dimensional structures at an atomic level, which is achieved through
the use of x-ray crystallographic or NMR approaches. To gain insight
into the transitional structural changes that occur during association,
recognition, or ligand binding, it is imperative to elucidate first the
structure of the free components and compare this to the structure of
the complex. The formation of interfaces in protein complexes is
achieved by hydrophobic interactions among nonpolar side chains,
hydrogen bonding interactions, electrostatic interactions (e.g., salt
bridges), and steric (van der Waals) interactions. Furthermore, the elec-
trostatic nature and shape constraints of the interacting partners within
a complex dictate to a great extent the mechanism by which the
optimum and more stable configuration is selected for recognition and
binding. In addition, the stability of the biomolecular association is
dependent on the inclusion or exclusion of solvent molecules within
the interacting interface.
In this respect, studies have been designed to elucidate the dynamics
that govern complex interactions between various complement compo-
nents, using a cross-disciplinary platform that integrates biochemical,
physicochemical, and computational methods. The interaction between
complement components iC3b/C3d and complement receptor type 2
(CR2) was used as a research prototype. Integrating available crystallo-
graphic data [7-9] with experimental findings that indicate a strong