# Modeling Transition Metal Ion Binding to Proteins

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $344,898

## Abstract

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.

## Key facts

- **NIH application ID:** 10880795
- **Project number:** 2R01GM130641-05A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** KENNETH M. MERZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $344,898
- **Award type:** 2
- **Project period:** 2019-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880795

## Citation

> US National Institutes of Health, RePORTER application 10880795, Modeling Transition Metal Ion Binding to Proteins (2R01GM130641-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10880795. Licensed CC0.

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