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Multi-Scale Design of Surveillance and Regulation Within the Complement System

Creative Commons 'BY-NC-ND' version 4.0 license

As part of innate immunity, the complement system surveils biological tissues for foreign surfaces such as bacterial membranes and generates an immune response over a time period of minutes to hours. At a molecular level, surveillance of bacterial or foreign surfaces is accomplished by actions of complement component 3b (C3b). This protein covalently bonds to such surfaces and can interact with other complement proteins to form an enzyme that upregulates the concentration of C3b. This feed forward amplification allows for an immune response to be surmounted in a brief period of time, but necessitates some regulation to prevent off-target effects and states of autoimmunity. Of all complement regulators, Factor H (FH) is most influential modulator of C3b activity, binding C3b and downregulating the concentration of C3 convertase. Herein, we study the structure-function relationship within and between the proteins C3b and FH in order to understand molecular mechanisms of disease and to engineer new molecules that monitor or modulate complement response. In these studies, we consider both static and dynamic structural features. From a static perspective, we have developed and applied a computational framework to predict electrostatic effects of mutations to study mechanisms of molecular interactions. From a dynamic perspective, we have leveraged biophysical methods to identify new functional conformational states and characterize conformational sampling of molecules. Importantly, these dynamical features range from harmonic fluctuations within a single conformational state that occur on the order of nanoseconds to domain motions that occur on the order of milliseconds. Given the range of time-scales that we study and the computational complexity associated with our methods, we use coarse grain methods to guide atomic simulations of protein dynamics for studies that involve domain rearrangements. Altogether, our studies contribute to a mechanistic understanding of complement structure and function, and we have engineered new molecules that target C3d and can be further optimized for therapeutic or diagnostic applications.

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