# Development and application of QM/MM methods for metalloenzymes

> **NIH NIH R01** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2020 · $330,000

## Abstract

Project Summary: Metalloenzymes play various important biological roles and therefore are major targets
for biomedical research. They also drive further development of computational methodologies that can strike
the proper balance of accuracy and sampling efficiency. Encouraged by progress made in the last funding
period, we continue to develop hybrid quantum mechanical/molecular mechanical (QM/MM) methods to un-
derstand the catalytic mechanism of metalloenzymes that play major roles in key biological processes such as
phosphoryl transfers and DNA replication. We will conduct extensive comparison of kinetic isotope effect (KIE)
and combinatorial mutation effects with experiments to calibrate our methodologies. The specific aims are:
1. Further develop an approximate Density Functional method (DFTB3) for transition metal ions in biological
applications. This involves: (i). improving the description of polarization and charge transfer of metal-ligand
interactions for charged ligands, guided by the Natural Bonding Orbital analysis; (ii). establishing high quality
benchmark dataset for metal-ligand interactions using highly correlated QM methods such as Density Matrix
Renormalization Group with Canonical Transform theory; (iii). including explicit on-site d - d interactions at the
orbital rather than population level in the framework of ligand-field theory. 2. Enhance mechanistic understand-
ing in the roles of metal ions in phosphoryl transfer enzymes. Through a combination of QM/MM free energy
and KIE calculations, we will: (i). explain why is the phosphoryl transfer transition state in phosphatase-1, but
not in alkaline phosphatase, substantially modified relative to solution, despite their generally similar bimetallic
active sites; establish whether the difference is dictated by the identity of the metal ions (Zn2+ vs. Mn2+), the
distance between them or the distribution of charges/dipoles in the active site; (ii). quantify the catalytic con-
tribution of the third “transient” Mg2+ to DNA polymerase ⌘ identified in recent time-resolved crystallography
studies, and establish the impact of this ion on the mechanism of 3'OH activation. 3. Integrate DFTB3/MM
and DFT/MM methodologies to provide a mechanistic understanding of co-operativity associated with various
“catalytic modules” identified in alkaline phosphatase through combinatorial mutation of key motifs in the active
site. The broad range of catalytic activities of these mutants, which span ten orders of magnitude in kcat/Km,
provides an unprecedented opportunity to test and calibrate QM/MM methods. In the long run, our efforts will
help establish “best-practice” QM/MM protocols that are able to aid rational design of metalloenzymes and
understand their evolution.

## Key facts

- **NIH application ID:** 9980920
- **Project number:** 5R01GM106443-09
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** Qiang Cui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $330,000
- **Award type:** 5
- **Project period:** 2013-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980920

## Citation

> US National Institutes of Health, RePORTER application 9980920, Development and application of QM/MM methods for metalloenzymes (5R01GM106443-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9980920. Licensed CC0.

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