This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cell biologies of many multicellular and other higher organisms are regulated by a broad family of Rel/NFkB proteins, with members of this protein family having been implicated in both normal and abnormal physiological pathways (e.g., immune and inflammatory responses, cell differentiation, apoptosis, oncogenesis). Many NFkB proteins are active as homo- or hetero-dimeric transcription factors that bind to kB-like DNA sequences with variable specificities and affinities; moreover, differences in binding of Rel/NFkB proteins to regulatory kB elements afford a means of differential gene regulation for target proteins (including protein families such as chemokines, cytokines, adhesion molecules, anti-microbial peptides, etc.). An NFkB variant known as c-Rel is one of the five abundant mammalian Rel proteins, and, intriguingly, a minimal number of changes to wild-type c-Rel convert it to an oncogenic variant (v-Rel) with considerably different biochemical properties and cellular functions.
The aim of the research proposed here is to elucidate the physico-chemical bases of these differences, with the overall goal of understanding how differences in the physical properties of two such similar proteins translate into their vastly different biochemical properties (particularly with regards to DNA-binding and indirect readout). In working towards these goals, a variety of computational methods -- including detailed electrostatics analyses, molecular dynamics (MD) simulations, and free energy calculations -- will be used to explore the salient differences between these proteins. Therefore, this particular proposal is a request for a small allocation of TeraGrid resources in order to further some work with MD simulations of wild-type and mutant NFkB proteins.
Showing the most recent 10 out of 292 publications
