Simulating aromatic ring flips & searching for unknown reaction coordinates using TPS
(2024) KFKM05 20241Biophysical Chemistry
- Abstract
- Today aromatic ring flipping has become a classic example to highlight the highly dynamic character of proteins. These dynamics occur when the aromatic side chains in phenylalanine and tyrosine turn 180o around its Cβ–Cγ axis, also known as its χ2 dihedral. Discovered in the 1970s’ these ring flippings are a common internal probe used in NMR spectroscopy to understand the protein interior dynamics surrounding these side chains. Until recently however the exact properties of this dynamic has remained largely unknown, but with recent development in NMR spectroscopy and molecular dynamics (MD) simulations more in-depth studies are now possible. In this study enhanced sampling techniques, called metadynamics and transition path sampling (TPS),... (More)
- Today aromatic ring flipping has become a classic example to highlight the highly dynamic character of proteins. These dynamics occur when the aromatic side chains in phenylalanine and tyrosine turn 180o around its Cβ–Cγ axis, also known as its χ2 dihedral. Discovered in the 1970s’ these ring flippings are a common internal probe used in NMR spectroscopy to understand the protein interior dynamics surrounding these side chains. Until recently however the exact properties of this dynamic has remained largely unknown, but with recent development in NMR spectroscopy and molecular dynamics (MD) simulations more in-depth studies are now possible. In this study enhanced sampling techniques, called metadynamics and transition path sampling (TPS), have been used to simulate this aromatic ring flipping in five individual aromatic side chains (F4, F22, F33, F45 and Y21), of the bovine pancreatic trypsin inhibitor.
These simulations created a collection of possible reactive pathways through which this flip could occur, which when analyzed has given new knowledge on how the flip actually works, and how the surrounding environment can affect the mechanism. This study builds upon previous research, which demonstrated that χ2 alone was insufficient as a reaction coordinate. By also incorporating the χ1 dihedral of the aromatic side chain as a reaction coordinate the characterization of the ring flip dynamics improved significantly. We continued that line of reasoning to investigate how effectively these coordinates describe the dynamics and to explore other potential factors that might have an impact. The results suggest that the coordinates χ1 and χ2 are not enough to describe the ring flipping motion, as the free-energy surfaces based on the χ1 and χ2 didn’t align with the observed dynamics. Environmental factors, like water exposure and surrounding cavity volume, are necessary in order to better define the mechanism. The result also indicates a significant difference in reaction time between the residues, with the longest taking 19.23 ps and the shortest taking 3.32 ps. Finally the results demonstrate the successful application of TPS to create a collection of diverse reactive pathways, allowing for the analysis of the slight variations in the mechanism. (Less) - Popular Abstract
- Proteins are so much more than just an important nutrient in food, necessary for muscle growth. Proteins are a cornerstone of life that allow cells to perform all biological functions. Everything from the largest of functions like the use of muscles to the smallest like the production of hormones is done by proteins. As such the understanding of proteins will give us intricate knowledge of how the human body works down to the cellular level, which is crucial for the development of products that will improve our lives.
Proteins are constructed by long chains of amino acids and are intricately folded as complex 3D structures. It’s these complex structures that give a protein its functions to a large degree, and part of this function... (More) - Proteins are so much more than just an important nutrient in food, necessary for muscle growth. Proteins are a cornerstone of life that allow cells to perform all biological functions. Everything from the largest of functions like the use of muscles to the smallest like the production of hormones is done by proteins. As such the understanding of proteins will give us intricate knowledge of how the human body works down to the cellular level, which is crucial for the development of products that will improve our lives.
Proteins are constructed by long chains of amino acids and are intricately folded as complex 3D structures. It’s these complex structures that give a protein its functions to a large degree, and part of this function comes from the structure's flexibility. This flexibility causes a protein's structure to change constantly, like a machine in constant motion, and the understanding of this motion has been the goal of many previous studies.
This study focuses on a small part of this motion known as “aromatic ring flipping”, occurring when an aromatic ring in the structure “flips” by turning 180o. This is a small structural change, with no known direct function for the protein. However studies have shown that when the motion occurs a cavity is created around the ring, which is necessary for the flip to happen. This cavity creation starts a sort of domino effect, where the entire protein structure can expand to accommodate the cavity. This results in the ring flip having an indirect effect on the protein, one whose function is not yet fully understood.
By simulating how the protein structure changes over time on an atomic level we have acquired a deeper understanding of how the motion affects the surrounding structure and vice versa. This study uses several different simulation methods to create a diverse collection of mechanisms through which the motion could occur. This collection is then analyzed to discover potential similarities, hinting at common factors in ring flipping, furthering our understanding of this motion. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9177796
- author
- Efraimsson, Emil LU
- supervisor
- organization
- course
- KFKM05 20241
- year
- 2024
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- biophysical chemistry, aromatic ring flip, transitional path sampling, molecular dynamics, BPTI
- language
- English
- id
- 9177796
- date added to LUP
- 2024-12-02 08:58:09
- date last changed
- 2024-12-02 08:58:09
@misc{9177796,
abstract = {{Today aromatic ring flipping has become a classic example to highlight the highly dynamic character of proteins. These dynamics occur when the aromatic side chains in phenylalanine and tyrosine turn 180o around its Cβ–Cγ axis, also known as its χ2 dihedral. Discovered in the 1970s’ these ring flippings are a common internal probe used in NMR spectroscopy to understand the protein interior dynamics surrounding these side chains. Until recently however the exact properties of this dynamic has remained largely unknown, but with recent development in NMR spectroscopy and molecular dynamics (MD) simulations more in-depth studies are now possible. In this study enhanced sampling techniques, called metadynamics and transition path sampling (TPS), have been used to simulate this aromatic ring flipping in five individual aromatic side chains (F4, F22, F33, F45 and Y21), of the bovine pancreatic trypsin inhibitor.
These simulations created a collection of possible reactive pathways through which this flip could occur, which when analyzed has given new knowledge on how the flip actually works, and how the surrounding environment can affect the mechanism. This study builds upon previous research, which demonstrated that χ2 alone was insufficient as a reaction coordinate. By also incorporating the χ1 dihedral of the aromatic side chain as a reaction coordinate the characterization of the ring flip dynamics improved significantly. We continued that line of reasoning to investigate how effectively these coordinates describe the dynamics and to explore other potential factors that might have an impact. The results suggest that the coordinates χ1 and χ2 are not enough to describe the ring flipping motion, as the free-energy surfaces based on the χ1 and χ2 didn’t align with the observed dynamics. Environmental factors, like water exposure and surrounding cavity volume, are necessary in order to better define the mechanism. The result also indicates a significant difference in reaction time between the residues, with the longest taking 19.23 ps and the shortest taking 3.32 ps. Finally the results demonstrate the successful application of TPS to create a collection of diverse reactive pathways, allowing for the analysis of the slight variations in the mechanism.}},
author = {{Efraimsson, Emil}},
language = {{eng}},
note = {{Student Paper}},
title = {{Simulating aromatic ring flips & searching for unknown reaction coordinates using TPS}},
year = {{2024}},
}