DEVELOPMENT OF A MULTI-SCALE CHEMICAL MODELING APPROACH TO HEME-CONTAINING ENZY

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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. Iron-containing heme proteins play a central role in many biological systems; binding small molecules for transport and facilitating electron transfer and apoptosis. The apparent simplicity of their active sites makes these systems ideal for structure-function studies. Yet, they are also complicated by the existence of multiple oxidation states (FeII, the ferrous state, FeIII, the ferric state and FeIV, the ferryl ion) as well as multiple spin states. For example, the ferric Hemoglobin I upon binding hydrogen peroxide (H2O2) could exist as a doublet (one unpaired electron) or a quartet (three unpaired electrons) and may even convert between the two states as it progresses from the bound complex to compound I (the ferryl ion). Clearly, using computational methods to describe the mechanism (and hence construct a detailed structure-function relationship) will require accurate electronic structure methods. Yet, the ability to sample plausible structures besides the crystal structure is also crucial to a full understanding of such systems. The most efficient way to sample alternative structures is through simulations (molecular dynamics (MD) or Monte Carlo (MC)) that employ classical molecular mechanics (MM) force fields.