Modeling Transition Metal Ion Binding to Proteins

Project Summary/Abstract 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 lags behind related studies on proteins that do not contain TM ions. To address this issue multiple groups have built models validated using varying criteria making it difficult to focus on 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, role of Fe(II)/Fe(III) in ferroptosis etc. remain a significant challenge to computationally address. Through the systematic development of robust computational models of TMs, hypotheses can be formed to address problems focused on TM ion biology at a level currently available for systems lacking TM ions. We propose that we can fundamentally advance the study of transition metal (TM) containing biological systems by developing a freely available centralized software “hub” containing multiple validated classical force field models for TM ions that will facilitate the routine and accurate modeling of the structure and thermodynamics of TMs bound to proteins and in aqueous solution. Our long-term goal is to advance TM modeling approaches, place them into the widely used AMBER simulation package and then validate and disseminate the various methodologies to address problems involving metalloproteins by both the experimental and computational communities. Moreover, in this proposal we hypothesize that our models will enhance our ability to design metal binding sites and provide molecular-level insights into TM ion transport. The fundamental biophysical and biochemical questions we are addressing are what controls the structure, function and dynamics of TM ion complexation and TM ion transport in proteins. Building on our success with developing class-leading bonded metal ion force fields we will create next generation models that can be exploited in understanding the structural and functional role of TMs in biology.