Modeling catalytic promiscuity in the alkaline phosphatase superfamily
Duarte, Fernanda ; Amrein, Beat Anton and Kamerlin, Shina Caroline Lynn LU
(2013)
In Physical chemistry chemical physics : PCCP
15(27).
p.77-11160
- Abstract
In recent years, it has become increasingly clear that promiscuity plays a key role in the evolution of new enzyme function. This finding has helped to elucidate fundamental aspects of molecular evolution. While there has been extensive experimental work on enzyme promiscuity, computational modeling of the chemical details of such promiscuity has traditionally fallen behind the advances in experimental studies, not least due to the nearly prohibitive computational cost involved in examining multiple substrates with multiple potential mechanisms and binding modes in atomic detail with a reasonable degree of accuracy. However, recent advances in both computational methodologies and power have allowed us to reach a stage in the field where... (More)
In recent years, it has become increasingly clear that promiscuity plays a key role in the evolution of new enzyme function. This finding has helped to elucidate fundamental aspects of molecular evolution. While there has been extensive experimental work on enzyme promiscuity, computational modeling of the chemical details of such promiscuity has traditionally fallen behind the advances in experimental studies, not least due to the nearly prohibitive computational cost involved in examining multiple substrates with multiple potential mechanisms and binding modes in atomic detail with a reasonable degree of accuracy. However, recent advances in both computational methodologies and power have allowed us to reach a stage in the field where we can start to overcome this problem, and molecular simulations can now provide accurate and efficient descriptions of complex biological systems with substantially less computational cost. This has led to significant advances in our understanding of enzyme function and evolution in a broader sense. Here, we will discuss currently available computational approaches that can allow us to probe the underlying molecular basis for enzyme specificity and selectivity, discussing the inherent strengths and weaknesses of each approach. As a case study, we will discuss recent computational work on different members of the alkaline phosphatase superfamily (AP) using a range of different approaches, showing the complementary insights they have provided. We have selected this particular superfamily, as it poses a number of significant challenges for theory, ranging from the complexity of the actual reaction mechanisms involved to the reliable modeling of the catalytic metal centers, as well as the very large system sizes. We will demonstrate that, through current advances in methodologies, computational tools can provide significant insight into the molecular basis for catalytic promiscuity, and, therefore, in turn, the mechanisms of protein functional evolution.
(Less)
- author
- Duarte, Fernanda
; Amrein, Beat Anton
and Kamerlin, Shina Caroline Lynn
LU
- publishing date
- 2013-07-21
- type
- Contribution to journal
- publication status
- published
- keywords
- Alkaline Phosphatase/chemistry, Biocatalysis, Models, Molecular, Molecular Dynamics Simulation, Monte Carlo Method, Quantum Theory
- in
- Physical chemistry chemical physics : PCCP
- volume
- 15
- issue
- 27
- pages
- 18 pages
- publisher
- Royal Society of Chemistry
- external identifiers
-
- scopus:84881084908
- pmid:23728154
- ISSN
- 1463-9084
- DOI
- 10.1039/c3cp51179k
- language
- English
- LU publication?
- no
- id
- 83c3e1a7-25b7-4aad-ad45-fa94f2b00c47
- date added to LUP
- 2025-01-11 22:00:24
- date last changed
- 2025-06-15 16:09:21
@article{83c3e1a7-25b7-4aad-ad45-fa94f2b00c47,
abstract = {{<p>In recent years, it has become increasingly clear that promiscuity plays a key role in the evolution of new enzyme function. This finding has helped to elucidate fundamental aspects of molecular evolution. While there has been extensive experimental work on enzyme promiscuity, computational modeling of the chemical details of such promiscuity has traditionally fallen behind the advances in experimental studies, not least due to the nearly prohibitive computational cost involved in examining multiple substrates with multiple potential mechanisms and binding modes in atomic detail with a reasonable degree of accuracy. However, recent advances in both computational methodologies and power have allowed us to reach a stage in the field where we can start to overcome this problem, and molecular simulations can now provide accurate and efficient descriptions of complex biological systems with substantially less computational cost. This has led to significant advances in our understanding of enzyme function and evolution in a broader sense. Here, we will discuss currently available computational approaches that can allow us to probe the underlying molecular basis for enzyme specificity and selectivity, discussing the inherent strengths and weaknesses of each approach. As a case study, we will discuss recent computational work on different members of the alkaline phosphatase superfamily (AP) using a range of different approaches, showing the complementary insights they have provided. We have selected this particular superfamily, as it poses a number of significant challenges for theory, ranging from the complexity of the actual reaction mechanisms involved to the reliable modeling of the catalytic metal centers, as well as the very large system sizes. We will demonstrate that, through current advances in methodologies, computational tools can provide significant insight into the molecular basis for catalytic promiscuity, and, therefore, in turn, the mechanisms of protein functional evolution.</p>}},
author = {{Duarte, Fernanda and Amrein, Beat Anton and Kamerlin, Shina Caroline Lynn}},
issn = {{1463-9084}},
keywords = {{Alkaline Phosphatase/chemistry; Biocatalysis; Models, Molecular; Molecular Dynamics Simulation; Monte Carlo Method; Quantum Theory}},
language = {{eng}},
month = {{07}},
number = {{27}},
pages = {{77--11160}},
publisher = {{Royal Society of Chemistry}},
series = {{Physical chemistry chemical physics : PCCP}},
title = {{Modeling catalytic promiscuity in the alkaline phosphatase superfamily}},
url = {{http://dx.doi.org/10.1039/c3cp51179k}},
doi = {{10.1039/c3cp51179k}},
volume = {{15}},
year = {{2013}},
}