Transition metal (TM) ions play myriad roles in biology and are present in >30% of structures in the PDB yet the accurate computational modeling of these ions is less evolved than for the ?organic? framework of proteins. Hence, the simulation of metalloprotein structure, function and dynamics is lagging behind related studies on proteins that do not contain structural or functional TM ions. To address this issue a Balkanized approach has been taken over the last several decades where multiple groups have built models validated based on varying criteria with many being unavailable or only available in specific packages further making it difficult to focus best practices. Because of this gap in the modeling of TM ions important biological problems associated with TM ion homeostasis, metal center assembly, TM/drug interactions, dynamics of ligand association and product dissociation in metalloenzymes, attacking pathogens using nutritional immunity via TM sequestration near infection sites, etc. are a significant challenge to address. Through the development of robust computational models of TMs these problems, amongst others, focused on metal ion biology will become as addressable as is currently possible for biological molecules lacking TM ions. Our over-arching goal is to develop validated classical force field models that are readily available that can routinely and accurately model the structure and thermodynamics of TMs bound to proteins and in aqueous solution in order to address critical biological questions involving metal ions. Our long-term goal is to incorporate a range of extant TM modeling approaches into AMBER and to then validate and disseminate the various methodologies for our own use and for that of the community. Moreover, in this proposal we will apply our validated models to simulate TM binding at model and at protein metal binding sites, explore aspects of TM ion homeostasis (TMIH) and provide molecular-level insights into Atomic Force Microscopy (AFM) single- molecule studies on metalloproteins. The fundamental overarching biophysical question we are addressing is: what is required to accurately and routinely model TMs and what are the molecular-level details of metal ion complexation in proteins. Building on our success with developing class-leading bonded metal ion force fields we will create next generation models (with a strong focus on nonbonded representations) that can be exploited in understanding the critical role of TMs in biological processes.
Transition metal (TM) ions play myriad roles in biology and are present in >30% of structures in the PDB yet the accurate computational modeling of these ions is less evolved than for the ?organic? framework of proteins. With the proposed advancement in modeling of TM ions important biological problems associated with TM ion homeostasis, metal center assembly, TM/drug interactions, dynamics of ligand association and product dissociation in metalloenzymes, attacking pathogens using nutritional immunity via TM sequestration near infection sites, etc. will now be able to be addressed. Through the development of robust computational models of TMs these problems amongst others focused on TM ion biology will become as addressable as is currently possible for biological molecules lacking TM ions thereby opening up the ability to better explore TM ion-associated health issues.
