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On the Origin of Protein Dynamics.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	On the Origin of Protein Dynamics./
作者:	Schafer, Joseph W.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	128 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
標題:	Physical chemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28649164
ISBN:	9798535502564

On the Origin of Protein Dynamics.
Schafer, Joseph W.

On the Origin of Protein Dynamics. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 128 p.

Source: Dissertations Abstracts International, Volume: 83-02, Section: B.

Thesis (Ph.D.)--The University of Arizona, 2021.

This item must not be sold to any third party vendors.

Computational enzyme design is a principal task for biophysical theorists. This problem remains elusive due to the multifaceted nature of studying enzymes: sequence stability, substrate affinity, chemistry, and product release each playsignificant roles in catalysis. Studying these aspects of enzymes spans a multitude of time scales and currently requires a multitude of algorithms. A static picture of enzymes' transition state will struggle to produce efficient enzymes. In thepast few decades, directed evolution has become a standard biochemical tool that iteratively improves a selected function of an amino acid sequence without the need for the researcher to understand the sequence-function relationship.Systems subjected to directed evolution provide valuable data on enzyme's sequence-function relationship and will lead to the discovery of design principles. The femtosecond dynamics associated with a series of retro-aldolase enzymes were studied in pursuit of these underlying principles. Directed evolution had changed the location of the active site in the scaffold, and we found that this new active site could support an alternative mechanism than was observed in the previous retro-aldolases. The alternative mechanism found in the most evolved enzyme contained a rate-promoting vibration. The incorporation of protein dynamics coupled to chemistry by directed evolution is considered strong evidence that dynamics must be considered for protein engineering. Further analysis of this system showed that directed evolution altered the hydrogen bonding network, in the latest variant, to have a preferred direction of energy transfer in the same direction as the previously identified rate promoting vibration.The second system of enzymes examined is tryptophan synthase. This system is a natural enzyme with an allosteric effect. Here the goal of directed evolution was to create a sequence that can catalyze the synthesis of tryptophan withoutthe need for the allosteric effector. In examining the fast protein dynamics associated with this system, we found evidence supporting previous experimental work describing how the mutations stabilize a catalytic conformation similar tothe closed state from the allosteric effect. It was also discovered that dynamic details of chemistry were altered to preserve the efficiency in the new sequence. Adopting more detailed and instructive theories of catalysis will be necessary going forward. As a whole, this work makes a strong case for the importance of protein dynamics in enzyme catalysis. In removing an allosteric effect, where preserving efficient chemistry is the goal, mutations favored smaller hydrophobic residues away from the active site. In completely redesigning an enzyme to have efficient chemistry, mutations favored larger, more polar residues. In both cases, fast protein dynamics play a significant role. Computational enzyme engineering will need to consider stability, affinity, product release, and fast protein dynamics coupled to chemistry for each mutation to rival directed evolution.

ISBN: 9798535502564Subjects--Topical Terms:

1981412
Physical chemistry.
Subjects--Index Terms:

Biophysics

On the Origin of Protein Dynamics.
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506 $a This item must not be sold to any third party vendors.
520 $a Computational enzyme design is a principal task for biophysical theorists. This problem remains elusive due to the multifaceted nature of studying enzymes: sequence stability, substrate affinity, chemistry, and product release each playsignificant roles in catalysis. Studying these aspects of enzymes spans a multitude of time scales and currently requires a multitude of algorithms. A static picture of enzymes' transition state will struggle to produce efficient enzymes. In thepast few decades, directed evolution has become a standard biochemical tool that iteratively improves a selected function of an amino acid sequence without the need for the researcher to understand the sequence-function relationship.Systems subjected to directed evolution provide valuable data on enzyme's sequence-function relationship and will lead to the discovery of design principles. The femtosecond dynamics associated with a series of retro-aldolase enzymes were studied in pursuit of these underlying principles. Directed evolution had changed the location of the active site in the scaffold, and we found that this new active site could support an alternative mechanism than was observed in the previous retro-aldolases. The alternative mechanism found in the most evolved enzyme contained a rate-promoting vibration. The incorporation of protein dynamics coupled to chemistry by directed evolution is considered strong evidence that dynamics must be considered for protein engineering. Further analysis of this system showed that directed evolution altered the hydrogen bonding network, in the latest variant, to have a preferred direction of energy transfer in the same direction as the previously identified rate promoting vibration.The second system of enzymes examined is tryptophan synthase. This system is a natural enzyme with an allosteric effect. Here the goal of directed evolution was to create a sequence that can catalyze the synthesis of tryptophan withoutthe need for the allosteric effector. In examining the fast protein dynamics associated with this system, we found evidence supporting previous experimental work describing how the mutations stabilize a catalytic conformation similar tothe closed state from the allosteric effect. It was also discovered that dynamic details of chemistry were altered to preserve the efficiency in the new sequence. Adopting more detailed and instructive theories of catalysis will be necessary going forward. As a whole, this work makes a strong case for the importance of protein dynamics in enzyme catalysis. In removing an allosteric effect, where preserving efficient chemistry is the goal, mutations favored smaller hydrophobic residues away from the active site. In completely redesigning an enzyme to have efficient chemistry, mutations favored larger, more polar residues. In both cases, fast protein dynamics play a significant role. Computational enzyme engineering will need to consider stability, affinity, product release, and fast protein dynamics coupled to chemistry for each mutation to rival directed evolution.
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650 4 $a Biophysics. $3 518360
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650 4 $a Evolution. $3 532919
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653 $a Computational chemistry
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