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Article ; Online: The shortest path method (SPM) webserver for computational enzyme design.

Casadevall, Guillem / Casadevall, Jordi / Duran, Cristina / Osuna, Sílvia

Protein engineering, design & selection : PEDS

2024 Volume 37

Abstract: SPMweb is the online webserver of the Shortest Path Map (SPM) tool for identifying the key conformationally-relevant positions of a given enzyme structure and dynamics. The server is built on top of the DynaComm.py code and enables the calculation and ... ...

Abstract	SPMweb is the online webserver of the Shortest Path Map (SPM) tool for identifying the key conformationally-relevant positions of a given enzyme structure and dynamics. The server is built on top of the DynaComm.py code and enables the calculation and visualization of the SPM pathways. SPMweb is easy-to-use as it only requires three input files: the three-dimensional structure of the protein of interest, and the two matrices (distance and correlation) previously computed from a Molecular Dynamics simulation. We provide in this publication information on how to generate the files for SPM construction even for non-expert users and discuss the most relevant parameters that can be modified. The tool is extremely fast (it takes less than one minute per job), thus allowing the rapid identification of distal positions connected to the active site pocket of the enzyme. SPM applications expand from computational enzyme design, especially if combined with other tools to identify the preferred substitution at the identified position, but also to rationalizing allosteric regulation, and even cryptic pocket identification for drug discovery. The simple user interface and setup make the SPM tool accessible to the whole scientific community. SPMweb is freely available for academia at http://spmosuna.com/.
MeSH term(s)	Allosteric Regulation ; Molecular Dynamics Simulation
Language	English
Publishing date	2024-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1466729-0
ISSN	1741-0134 ; 1741-0126
ISSN (online)	1741-0134
ISSN	1741-0126
DOI	10.1093/protein/gzae005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: AlphaFold2 and Deep Learning for Elucidating Enzyme Conformational Flexibility and Its Application for Design.

Casadevall, Guillem / Duran, Cristina / Osuna, Sílvia

JACS Au

2023 Volume 3, Issue 6, Page(s) 1554–1562

Abstract: The recent success of AlphaFold2 (AF2) and other deep learning (DL) tools in accurately predicting the folded three-dimensional (3D) structure of proteins and enzymes has revolutionized the structural biology and protein design fields. The 3D structure ... ...

Abstract	The recent success of AlphaFold2 (AF2) and other deep learning (DL) tools in accurately predicting the folded three-dimensional (3D) structure of proteins and enzymes has revolutionized the structural biology and protein design fields. The 3D structure indeed reveals key information on the arrangement of the catalytic machinery of enzymes and which structural elements gate the active site pocket. However, comprehending enzymatic activity requires a detailed knowledge of the chemical steps involved along the catalytic cycle and the exploration of the multiple thermally accessible conformations that enzymes adopt when in solution. In this Perspective, some of the recent studies showing the potential of AF2 in elucidating the conformational landscape of enzymes are provided. Selected examples of the key developments of AF2-based and DL methods for protein design are discussed, as well as a few enzyme design cases. These studies show the potential of AF2 and DL for allowing the routine computational design of efficient enzymes.
Language	English
Publishing date	2023-06-06
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2691-3704
ISSN (online)	2691-3704
DOI	10.1021/jacsau.3c00188
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Article: Retracing the Rapid Evolution of an Herbicide-Degrading Enzyme by Protein Engineering.

Busch, Markus R / Drexler, Lukas / Mahato, Dhani Ram / Hiefinger, Caroline / Osuna, Sílvia / Sterner, Reinhard

ACS catalysis

2024 Volume 13, Issue 23, Page(s) 15558–15571

Abstract: The mechanisms underlying the rapid evolution of novel enzymatic activities from promiscuous side activities are poorly understood. Recently emerged enzymes catalyzing the catabolic degradation of xenobiotic substances that have been spread out into the ... ...

Abstract	The mechanisms underlying the rapid evolution of novel enzymatic activities from promiscuous side activities are poorly understood. Recently emerged enzymes catalyzing the catabolic degradation of xenobiotic substances that have been spread out into the environment during the last decades provide an exquisite opportunity to study these mechanisms. A prominent example is the herbicide atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine), which is degraded through a number of enzymatic reactions constituting the Atz pathway. Here, we analyzed the evolution of the hydroxyatrazine ethylaminohydrolase AtzB, a Zn(II)-dependent metalloenzyme that adopts the amidohydrolase fold and catalyzes the second step of the Atz pathway. We searched for promiscuous side activities of AtzB, which might point to the identity of its progenitor. These investigations revealed that AtzB has low promiscuous guanine deaminase activity. Furthermore, we found that the two closest AtzB homologues, which have not been functionally annotated up to now, are guanine deaminases with modest promiscuous hydroxyatrazine hydrolase activity. Based on sequence comparisons with the closest AtzB homologues, the guanine deaminase activity of AtzB could be increased by three orders of magnitude through the introduction of only four active site mutations. Interestingly, introducing the inverse four mutations into the AtzB homologues significantly enhanced their hydroxyatrazine hydrolase activity, and in one case is even equivalent to that of wild-type AtzB. Molecular dynamics simulations elucidated the structural and molecular basis for the mutation-induced activity changes. The example of AtzB highlights how novel enzymes with high catalytic proficiency can evolve from low promiscuous side activities by only few mutational events within a short period of time.
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ISSN	2155-5435
ISSN	2155-5435
DOI	10.1021/acscatal.3c04010
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Article ; Online: Brave new surfactant world revisited by thermoalkalophilic lipases: computational insights into the role of SDS as a substrate analog.

Shehata, Mohamed / Ünlü, Aişe / Iglesias-Fernández, Javier / Osuna, Sílvia / Sezerman, O Ugur / Timucin, Emel

Physical chemistry chemical physics : PCCP

2023 Volume 25, Issue 3, Page(s) 2234–2247

Abstract: Non-ionic surfactants were shown to stabilize the active conformation of thermoalkalophilic lipases by mimicking the lipid substrate while the catalytic interactions formed by anionic surfactants have not been well characterized. In this study, we ... ...

Abstract	Non-ionic surfactants were shown to stabilize the active conformation of thermoalkalophilic lipases by mimicking the lipid substrate while the catalytic interactions formed by anionic surfactants have not been well characterized. In this study, we combined μs-scale molecular dynamics (MD) simulations and lipase activity assays to analyze the effect of ionic surfactant, sodium dodecyl sulfate (SDS), on the structure and activity of thermoalkalophilic lipases. Both the open and closed lipase conformations that differ in geometry were recruited to the MD analysis to provide a broader understanding of the molecular effect of SDS on the lipase structure. Simulations at 298 K showed the potential of SDS for maintaining the active lipase through binding to the
MeSH term(s)	Surface-Active Agents/chemistry ; Lipase/chemistry ; Molecular Dynamics Simulation ; Sodium Dodecyl Sulfate ; Temperature ; Pulmonary Surfactants
Chemical Substances	Surface-Active Agents ; Lipase (EC 3.1.1.3) ; Sodium Dodecyl Sulfate (368GB5141J) ; Pulmonary Surfactants
Language	English
Publishing date	2023-01-18
Publishing country	England
Document type	Journal Article
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/d2cp05093e
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Article ; Online: Estimating conformational heterogeneity of tryptophan synthase with a template-based Alphafold2 approach.

Casadevall, Guillem / Duran, Cristina / Estévez-Gay, Miquel / Osuna, Sílvia

Protein science : a publication of the Protein Society

2022 Volume 31, Issue 10, Page(s) e4426

Abstract: The three-dimensional structure of the enzymes provides very relevant information on the arrangement of the catalytic machinery and structural elements gating the active site pocket. The recent success of the neural network Alphafold2 in predicting the ... ...

Abstract	The three-dimensional structure of the enzymes provides very relevant information on the arrangement of the catalytic machinery and structural elements gating the active site pocket. The recent success of the neural network Alphafold2 in predicting the folded structure of proteins from the primary sequence with high levels of accuracy has revolutionized the protein design field. However, the application of Alphafold2 for understanding and engineering function directly from the obtained single static picture is not straightforward. Indeed, understanding enzymatic function requires the exploration of the ensemble of thermally accessible conformations that enzymes adopt in solution. In the present study, we evaluate the potential of Alphafold2 in assessing the effect of the mutations on the conformational landscape of the beta subunit of tryptophan synthase (TrpB). Specifically, we develop a template-based Alphafold2 approach for estimating the conformational heterogeneity of several TrpB enzymes, which is needed for enhanced stand-alone activity. Our results show the potential of Alphafold2, especially if combined with molecular dynamics simulations, for elucidating the changes induced by mutation in the conformational landscapes at a rather reduced computational cost, thus revealing its plausible application in computational enzyme design.
MeSH term(s)	Catalysis ; Catalytic Domain ; Protein Conformation ; Proteins ; Tryptophan Synthase/chemistry
Chemical Substances	Proteins ; Tryptophan Synthase (EC 4.2.1.20)
Language	English
Publishing date	2022-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4426
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Article ; Online: Harnessing the Structure and Dynamics of the Squalene-Hopene Cyclase for (-)-Ambroxide Production.

Schneider, Andreas / Curado, Christian / Lystbaek, Thomas B / Osuna, Sílvia / Hauer, Bernhard

Angewandte Chemie (International ed. in English)

2023 Volume 62, Issue 22, Page(s) e202301607

Abstract: Terpene cyclases offer enormous synthetic potential, given their unique ability to forge complex hydrocarbon scaffolds from achiral precursors within a single cationic rearrangement cascade. Harnessing their synthetic power, however, has proved to be ... ...

Abstract	Terpene cyclases offer enormous synthetic potential, given their unique ability to forge complex hydrocarbon scaffolds from achiral precursors within a single cationic rearrangement cascade. Harnessing their synthetic power, however, has proved to be challenging owing to their generally low catalytic performance. In this study, we unveiled the catalytic potential of the squalene-hopene cyclase (SHC) by harnessing its structure and dynamics. First, we synergistically tailored the active site and entrance tunnel of the enzyme to generate a 397-fold improved (-)-ambroxide synthase. Our computational investigations explain how the introduced mutations work in concert to improve substrate acquisition, flow, and chaperoning. Kinetics, however, showed terpene-induced inactivation of the membrane-bound SHC to be the major turnover limitation in vivo. Merging this insight with the improved and stereoselective catalysis of the enzyme, we applied a feeding strategy to exceed 10
MeSH term(s)	Intramolecular Transferases/genetics ; Intramolecular Transferases/metabolism ; Terpenes ; Catalytic Domain ; Catalysis ; Squalene ; Cyclization
Chemical Substances	squalene-hopene cyclase (EC 5.4.99.-) ; Intramolecular Transferases (EC 5.4.-) ; Terpenes ; Squalene (7QWM220FJH)
Language	English
Publishing date	2023-04-18
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202301607
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Article: Time Evolution of the Millisecond Allosteric Activation of Imidazole Glycerol Phosphate Synthase

Calvó-Tusell, Carla / Maria-Solano, Miguel A. / Osuna, Sílvia / Feixas, Ferran

Journal of the American Chemical Society. 2022 Apr. 12, v. 144, no. 16

2022

Abstract: Deciphering the molecular mechanisms of enzymatic allosteric regulation requires the structural characterization of functional states and also their time evolution toward the formation of the allosterically activated ternary complex. The transient nature ...

Abstract	Deciphering the molecular mechanisms of enzymatic allosteric regulation requires the structural characterization of functional states and also their time evolution toward the formation of the allosterically activated ternary complex. The transient nature and usually slow millisecond time scale interconversion between these functional states hamper their experimental and computational characterization. Here, we combine extensive molecular dynamics simulations, enhanced sampling techniques, and dynamical networks to describe the allosteric activation of imidazole glycerol phosphate synthase (IGPS) from the substrate-free form to the active ternary complex. IGPS is a heterodimeric bienzyme complex whose HisH subunit is responsible for hydrolyzing glutamine and delivering ammonia for the cyclase activity in HisF. Despite significant advances in understanding the underlying allosteric mechanism, essential molecular details of the long-range millisecond allosteric activation of IGPS remain hidden. Without using a priori information of the active state, our simulations uncover how IGPS, with the allosteric effector bound in HisF, spontaneously captures glutamine in a catalytically inactive HisH conformation, subsequently attains a closed HisF:HisH interface, and finally forms the oxyanion hole in HisH for efficient glutamine hydrolysis. We show that the combined effector and substrate binding dramatically decreases the conformational barrier associated with oxyanion hole formation, in line with the experimentally observed 4500-fold activity increase in glutamine hydrolysis. The allosteric activation is controlled by correlated time-evolving dynamic networks connecting the effector and substrate binding sites. This computational strategy tailored to describe millisecond events can be used to rationalize the effect of mutations on the allosteric regulation and guide IGPS engineering efforts.
Keywords	ammonia ; glutamine ; glycerol ; hydrolysis ; imidazole ; molecular dynamics ; oxyanions ; phosphates
Language	English
Dates of publication	2022-0412
Size	p. 7146-7159.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.1c12629
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Time Evolution of the Millisecond Allosteric Activation of Imidazole Glycerol Phosphate Synthase.

Calvó-Tusell, Carla / Maria-Solano, Miguel A / Osuna, Sílvia / Feixas, Ferran

Journal of the American Chemical Society

2022 Volume 144, Issue 16, Page(s) 7146–7159

Abstract	Deciphering the molecular mechanisms of enzymatic allosteric regulation requires the structural characterization of functional states and also their time evolution toward the formation of the allosterically activated ternary complex. The transient nature and usually slow millisecond time scale interconversion between these functional states hamper their experimental and computational characterization. Here, we combine extensive molecular dynamics simulations, enhanced sampling techniques, and dynamical networks to describe the allosteric activation of imidazole glycerol phosphate synthase (IGPS) from the substrate-free form to the active ternary complex. IGPS is a heterodimeric bienzyme complex whose HisH subunit is responsible for hydrolyzing glutamine and delivering ammonia for the cyclase activity in HisF. Despite significant advances in understanding the underlying allosteric mechanism, essential molecular details of the long-range millisecond allosteric activation of IGPS remain hidden. Without using
MeSH term(s)	Allosteric Regulation ; Aminohydrolases/chemistry ; Aminohydrolases/genetics ; Aminohydrolases/metabolism ; Binding Sites ; Glutamine/metabolism
Chemical Substances	Glutamine (0RH81L854J) ; imidazole glycerol phosphate synthase (EC 3.5.1.-) ; Aminohydrolases (EC 3.5.4.-)
Language	English
Publishing date	2022-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.1c12629
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Article ; Online: C-H Bonds as Functional Groups: Simultaneous Generation of Multiple Stereocenters by Enantioselective Hydroxylation at Unactivated Tertiary C-H Bonds.

Palone, Andrea / Casadevall, Guillem / Ruiz-Barragan, Sergi / Call, Arnau / Osuna, Sílvia / Bietti, Massimo / Costas, Miquel

Journal of the American Chemical Society

2023 Volume 145, Issue 29, Page(s) 15742–15753

Abstract: Enantioselective C-H oxidation is a standing chemical challenge foreseen as a powerful tool to transform readily available organic molecules into precious oxygenated building blocks. Here, we describe a catalytic enantioselective hydroxylation of ... ...

Abstract	Enantioselective C-H oxidation is a standing chemical challenge foreseen as a powerful tool to transform readily available organic molecules into precious oxygenated building blocks. Here, we describe a catalytic enantioselective hydroxylation of tertiary C-H bonds in cyclohexane scaffolds with H
Language	English
Publishing date	2023-07-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.2c10148
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Article ; Online: Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary

Castelli, Matteo / Marchetti, Filippo / Osuna, Sílvia / F Oliveira, A Sofia / Mulholland, Adrian J / Serapian, Stefano A / Colombo, Giorgio

Journal of the American Chemical Society

2023 Volume 146, Issue 1, Page(s) 901–919

Abstract: Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating in an ... ...

Abstract	Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating in an unperturbed protein are often unintuitively reshaped whenever biochemical perturbations arise (
MeSH term(s)	Molecular Dynamics Simulation ; Proteins/chemistry ; Catalytic Domain ; Guanosine Triphosphate/metabolism ; Allosteric Regulation
Chemical Substances	Proteins ; Guanosine Triphosphate (86-01-1)
Language	English
Publishing date	2023-12-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.3c11396
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