# Modeling Transition Metal Ion Binding to Proteins

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $319,909

## 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 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.

## Key facts

- **NIH application ID:** 10003344
- **Project number:** 5R01GM130641-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Hasan Metin Aktulga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $319,909
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003344

## Citation

> US National Institutes of Health, RePORTER application 10003344, Modeling Transition Metal Ion Binding to Proteins (5R01GM130641-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10003344. Licensed CC0.

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