Leo Caves | Independent Researcher (original) (raw)

Papers by Leo Caves

Research paper thumbnail of Activating the p53 anti-cancer pathway by targeting the MDM2/MDMX dimer interface with short peptide segments: a computational peptide design experiment

Molecular Systems Design & Engineering

Systematic mutation of the I485 and I489 residues of the KEIQLVIKVFI489A peptide leads to 14 muta... more Systematic mutation of the I485 and I489 residues of the KEIQLVIKVFI489A peptide leads to 14 mutant peptides that show at least three-fold preferential binding to the MDM2/MDMX interface (ΔΔG ∼ −3.00 kcal mol−1) lower than the KEIQLVIKVFI489A peptide (ΔΔG = −1.02 kcal mol−1).

Research paper thumbnail of Distributions of the sugar psuedorotation angles P1, P2 and backbone torsion pairs; (ɛ−γ), (α,γ) in each energy valley

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved P1 and α are shown in green while P2 and γ are in red. Positions of corresponding minima are indicated by dotted lines. Densities are based on a GC subspace PES.

Research paper thumbnail of Disruption of 3CLpro protease self-association by short peptides as a potential route to broad spectrum coronavirus inhibitors

Journal of Biomolecular Structure and Dynamics, 2021

Coronaviruses have posed a persistent threat to human health over the last two decades. Despite t... more Coronaviruses have posed a persistent threat to human health over the last two decades. Despite the accumulated knowledge about coronavirus-related pathogens, development of an effective treatment for its new variant COVID-19 is highly challenging. For the highly-conserved and main coronavirus protease 3CLpro, dimerization is known to be essential for its catalytic activity and thereby for virus proliferation. Here, we assess the potential of short peptide segments to disrupt dimerization of the 3CLpro protease as a route to block COVID-19 proliferation. Based on the X-ray structure of the 3CLpro dimer, we identified the SPSGVY126QCAMRP dodecapeptide segment as overlapping the hotspot regions on the 3CLpro dimer interface. Using computational blind docking of the peptide to the 3CLpro monomer, we found that the SPSGVY126QCAMRP peptide has favourable thermodynamic binding (ΔG= -5.93 kcal/mol) to the hotspot regions at the 3CLpro dimer interface. Importantly, the peptide was also found to preferentially bind to the hotspot regions compared to other potential binding sites lying away from the dimer interface (ΔΔG=-1.31 kcal/mol). Docking of peptides corresponding to systematic mutation of the V125 and Y126 residues led to the identification of seven peptides, SPSGHAQCAMRP, SPSGVTQCAMRP, SPSGKPQCAMRP, SPSGATQCAMRP, SPSGWLQCAMRP, SPSGAPQCAMRP and SPSGHPQCAMRP, that outperform the wild-type SPSGVY126QCAMRP peptide in terms of preferential binding to the 3CLpro dimer interface. These peptides have the potential to disrupt 3CLpro dimerization and therefore could provide lead structures for the development of broad spectrum COVID-19 inhibitors.Communicated by Ramaswamy H. Sarma.

Research paper thumbnail of Human Insulin Hexamers with Chain B His Mutated to Tyr Complexed with Phenol

Research paper thumbnail of Molecular Evolutionary Convergence of the Flight Muscle Protein Arthrin in Diptera and Hemiptera

Molecular Biology and Evolution, 2003

Uniquely, the asynchronous flight muscle myofibrils of many insects contain arthrin, a stable 1:1... more Uniquely, the asynchronous flight muscle myofibrils of many insects contain arthrin, a stable 1:1 conjugate between actin and ubiquitin. The function of arthrin is still unknown. Here we survey for the presence of arthrin in 63 species of insect across nine orders using Western blotting. Analysis of the evolutionary distribution shows that arthrin has evolved a limited number of times but at least once in the Diptera and once in the Hemiptera. However, the presence of arthrin does not correlate with any observed common features of flight mechanism, natural history, or morphology. We also identify the site of the isopeptide bond in arthrin from Drosophila melanogaster (Diptera) and Lethocerus griseus (Hemiptera) using mass spectrometry. In both species, the isopeptide bond is formed between lysine 118 of the actin and the C-terminal glycine 76 of ubiquitin. Thus, not only the ubiquitination of actin but also the site of the isopeptide bond has evolved convergently in Diptera and Hemiptera. In terms of the actin monomer, lysine 118 is near neither the binding sites of the major actin-binding proteins, myosin, tropomyosin, or the troponins, nor the actin polymerization sites. However, molecular modeling supports the idea that ubiquitin bound to an actin in one F-actin strand might be able to interact with tropomyosin bound to the actin monomers of the other strand and thereby interfere with thin filament regulation.

Research paper thumbnail of Design of peptide-based coronavirus inhibitors that target disruption of 3CLpro protease self-association

Molecular Systems Design & Engineering

The SGFRKMAF peptide disrupts 3CLpro dimerization via a dual mechanism: binding to the interface ... more The SGFRKMAF peptide disrupts 3CLpro dimerization via a dual mechanism: binding to the interface (blue) and/or the groove between domains II and III (magenta), with an equilibrium constant, Kin/out ∼0.12. M6F&F8S mutation leads to Kin/out ∼2.5 at 310 K.

Research paper thumbnail of Visualization of a room temperature solvated molecular dynamics simulation of the duplex hexamer d(ATATAT) initiated from the canonical B-form

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved Projection of the trajectory of the middle base step of 'strand a' into the PCS derived from duplex DNA crystal structures. () A scatter plot of the trajectory projection within the PCS. BI state is shown in green, A-form in black, BII-form in orange; BII-form is in red. Conformations with mixed sugar puckers (i.e. P·P or P·P) in yellow. () Density plot of the trajectory projection shown in three perpendicular planes: from top to bottom; PC1–PC2 plane at PC3 = 40, PC1–PC3 plane at PC2 = 0 and PC2–PC3 plane at PC1 = −100. In each plane, the axes extend from −300 to 300 and the tick marks are placed at 20° increments. Relative densities are indicated by gradual change from black (high density) to white (zero density). The trajectory boundary (almost zero density) is indicated by a dashed line. () d(AT) PES slices in the planes indicated in (b) with the conformational states indicated in (a) superposed. The colour ramp is similar to that used in .

Research paper thumbnail of Trajectories of the steepest descent path of the BI-to-A interconversion computed for a duplex d(AT) step (shown in magenta) projected onto the PES of a single-strand AT dinucleotide

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved () In a plane containing the two minima and the saddle points. () Alternative view of the trajectory in the PCS with the PES shown in the slice of the PC1–PC2 plane containing the transition states. The trajectories of the two individual strands of the duplex are very similar and not distinguishable at the resolution presented.

Research paper thumbnail of The torsion angle variables of the dinucleotide backbone fragment included in the PCA (see )

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved The conformation of the sugar–phosphate backbone is conventionally defined by six torsion angles labelled α to γ, with χ describing the N-C1′ glycosyl linkage to the bases. For each sugar, there are five torsion angles ν to ν in the furanose ring [conventionally described via a pseudorotation phase angle ()].

Research paper thumbnail of Total potential energy slices in the principal conformational plane spanned by PC1 and PC2 for a GC dinucleotide monophosphate fragment using a radius-dependent dielectric model (RDIE) for the electrostatic term of the potential energy function

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved Low energy regions are labelled from 1 to 6 on the lowest energy slice.

Research paper thumbnail of CES Winter School 2020. 'Sustainable development, complexity and change: thinking and practices for the SDG and other objectives'. Descriptive and evaluation summary report

Research paper thumbnail of (Gardening) Gardening: A Relational Framework for Complex Thinking About Complex Systems

For positive outcomes to be achieved in the management of change in complex systems, our modes of... more For positive outcomes to be achieved in the management of change in complex systems, our modes of thinking need to be congruent with the complexity of the targeted systems. In this chapter, we draw inspiration from the concept of gardening, conceived as a systemic activity of managing relations or the process by which a gardener relates to the relations of a complex system, to develop a relational thinking framework for complex thinking applied to change in complex systems. This framework is based on a relational worldview of interventions, as systemic activities aimed at change in complex systems. We propose a heuristic, in the form of a recursive relational thinking method, which can be used to explore different configurations of relations that represent abstract entities within a modelworld. Further we suggest that these configurations of relations can be the base for a corresponding storyworld, to assist in the narration of change in complex systems. We present this general abst...

Research paper thumbnail of Discussion and Comment (Time Will Tell)

Richard Walsh, Leo Caves, Ana Teixeira de Melo, Susan Stepney, and Emma Uprichard in discussion o... more Richard Walsh, Leo Caves, Ana Teixeira de Melo, Susan Stepney, and Emma Uprichard in discussion on an earlier version of “Time Will Tell: Narrative Expressions of Time in a Complex World”

Research paper thumbnail of Ching, Y. H. et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nature Genet. 37, 423-428

Research paper thumbnail of Automatic Design of Scheduling Policies for Dynamic Multi-objective Job Shop Scheduling via Cooperative Coevolution Genetic Programming..................................................... S. Nguyen, M. Zhang, M. Johnston, and K. Chen Tan 193 An Improved Differential Evolution Algorithm for Pract...

Research paper thumbnail of Stem Cell Reports

Research paper thumbnail of MBO (N) D-A new multibody dynamics methodology for the modeling of macromolecules as substructures

Research paper thumbnail of Special issue on the frontiers of natural computing

Natural Computing, 2013

ABSTRACT This paper extends a recent abstract, tunable model of genomic structural change within ... more ABSTRACT This paper extends a recent abstract, tunable model of genomic structural change within the cell lifecycle and explores its use with simulated evolution. A Boolean model of genetic regulatory networks has been presented to include changes in structure ...

Research paper thumbnail of Building Foundations for Complex Thinking: A call for inter/transdisciplinary collaborations

Research paper thumbnail of Pathways towards knowledge integration: orchestrating interventions in the inter/transdisciplinary ecosystem

Different forms of knowledge and practices of knowing operate at different levels of organisation... more Different forms of knowledge and practices of knowing operate at different levels of organisation within society. Scientific knowledge is but one form of knowing, but its development under a culture of disciplinisation and increasing specialisation has led to its fragmentation and blinded science to the possibilities offered by the integration of knowledge. Humanity's biggest challenges call for organised collective action, informed by the most complex forms of thinking. Interdisciplinarity and transdisciplinarity are privileged routes for rich knowledge construction and integration. There is a pressing need for efforts directed toward the intentional construction of a culture where interdisciplinary and, transdisciplinary practices may flourish. However, we believe significant change will only occur through the orchestration of a set of activities that attend to the complexity of knowledge construction and integration as emergent outcomes of a complex network of processes and r...

Research paper thumbnail of Activating the p53 anti-cancer pathway by targeting the MDM2/MDMX dimer interface with short peptide segments: a computational peptide design experiment

Molecular Systems Design & Engineering

Systematic mutation of the I485 and I489 residues of the KEIQLVIKVFI489A peptide leads to 14 muta... more Systematic mutation of the I485 and I489 residues of the KEIQLVIKVFI489A peptide leads to 14 mutant peptides that show at least three-fold preferential binding to the MDM2/MDMX interface (ΔΔG ∼ −3.00 kcal mol−1) lower than the KEIQLVIKVFI489A peptide (ΔΔG = −1.02 kcal mol−1).

Research paper thumbnail of Distributions of the sugar psuedorotation angles P1, P2 and backbone torsion pairs; (ɛ−γ), (α,γ) in each energy valley

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved P1 and α are shown in green while P2 and γ are in red. Positions of corresponding minima are indicated by dotted lines. Densities are based on a GC subspace PES.

Research paper thumbnail of Disruption of 3CLpro protease self-association by short peptides as a potential route to broad spectrum coronavirus inhibitors

Journal of Biomolecular Structure and Dynamics, 2021

Coronaviruses have posed a persistent threat to human health over the last two decades. Despite t... more Coronaviruses have posed a persistent threat to human health over the last two decades. Despite the accumulated knowledge about coronavirus-related pathogens, development of an effective treatment for its new variant COVID-19 is highly challenging. For the highly-conserved and main coronavirus protease 3CLpro, dimerization is known to be essential for its catalytic activity and thereby for virus proliferation. Here, we assess the potential of short peptide segments to disrupt dimerization of the 3CLpro protease as a route to block COVID-19 proliferation. Based on the X-ray structure of the 3CLpro dimer, we identified the SPSGVY126QCAMRP dodecapeptide segment as overlapping the hotspot regions on the 3CLpro dimer interface. Using computational blind docking of the peptide to the 3CLpro monomer, we found that the SPSGVY126QCAMRP peptide has favourable thermodynamic binding (ΔG= -5.93 kcal/mol) to the hotspot regions at the 3CLpro dimer interface. Importantly, the peptide was also found to preferentially bind to the hotspot regions compared to other potential binding sites lying away from the dimer interface (ΔΔG=-1.31 kcal/mol). Docking of peptides corresponding to systematic mutation of the V125 and Y126 residues led to the identification of seven peptides, SPSGHAQCAMRP, SPSGVTQCAMRP, SPSGKPQCAMRP, SPSGATQCAMRP, SPSGWLQCAMRP, SPSGAPQCAMRP and SPSGHPQCAMRP, that outperform the wild-type SPSGVY126QCAMRP peptide in terms of preferential binding to the 3CLpro dimer interface. These peptides have the potential to disrupt 3CLpro dimerization and therefore could provide lead structures for the development of broad spectrum COVID-19 inhibitors.Communicated by Ramaswamy H. Sarma.

Research paper thumbnail of Human Insulin Hexamers with Chain B His Mutated to Tyr Complexed with Phenol

Research paper thumbnail of Molecular Evolutionary Convergence of the Flight Muscle Protein Arthrin in Diptera and Hemiptera

Molecular Biology and Evolution, 2003

Uniquely, the asynchronous flight muscle myofibrils of many insects contain arthrin, a stable 1:1... more Uniquely, the asynchronous flight muscle myofibrils of many insects contain arthrin, a stable 1:1 conjugate between actin and ubiquitin. The function of arthrin is still unknown. Here we survey for the presence of arthrin in 63 species of insect across nine orders using Western blotting. Analysis of the evolutionary distribution shows that arthrin has evolved a limited number of times but at least once in the Diptera and once in the Hemiptera. However, the presence of arthrin does not correlate with any observed common features of flight mechanism, natural history, or morphology. We also identify the site of the isopeptide bond in arthrin from Drosophila melanogaster (Diptera) and Lethocerus griseus (Hemiptera) using mass spectrometry. In both species, the isopeptide bond is formed between lysine 118 of the actin and the C-terminal glycine 76 of ubiquitin. Thus, not only the ubiquitination of actin but also the site of the isopeptide bond has evolved convergently in Diptera and Hemiptera. In terms of the actin monomer, lysine 118 is near neither the binding sites of the major actin-binding proteins, myosin, tropomyosin, or the troponins, nor the actin polymerization sites. However, molecular modeling supports the idea that ubiquitin bound to an actin in one F-actin strand might be able to interact with tropomyosin bound to the actin monomers of the other strand and thereby interfere with thin filament regulation.

Research paper thumbnail of Design of peptide-based coronavirus inhibitors that target disruption of 3CLpro protease self-association

Molecular Systems Design & Engineering

The SGFRKMAF peptide disrupts 3CLpro dimerization via a dual mechanism: binding to the interface ... more The SGFRKMAF peptide disrupts 3CLpro dimerization via a dual mechanism: binding to the interface (blue) and/or the groove between domains II and III (magenta), with an equilibrium constant, Kin/out ∼0.12. M6F&F8S mutation leads to Kin/out ∼2.5 at 310 K.

Research paper thumbnail of Visualization of a room temperature solvated molecular dynamics simulation of the duplex hexamer d(ATATAT) initiated from the canonical B-form

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved Projection of the trajectory of the middle base step of 'strand a' into the PCS derived from duplex DNA crystal structures. () A scatter plot of the trajectory projection within the PCS. BI state is shown in green, A-form in black, BII-form in orange; BII-form is in red. Conformations with mixed sugar puckers (i.e. P·P or P·P) in yellow. () Density plot of the trajectory projection shown in three perpendicular planes: from top to bottom; PC1–PC2 plane at PC3 = 40, PC1–PC3 plane at PC2 = 0 and PC2–PC3 plane at PC1 = −100. In each plane, the axes extend from −300 to 300 and the tick marks are placed at 20° increments. Relative densities are indicated by gradual change from black (high density) to white (zero density). The trajectory boundary (almost zero density) is indicated by a dashed line. () d(AT) PES slices in the planes indicated in (b) with the conformational states indicated in (a) superposed. The colour ramp is similar to that used in .

Research paper thumbnail of Trajectories of the steepest descent path of the BI-to-A interconversion computed for a duplex d(AT) step (shown in magenta) projected onto the PES of a single-strand AT dinucleotide

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved () In a plane containing the two minima and the saddle points. () Alternative view of the trajectory in the PCS with the PES shown in the slice of the PC1–PC2 plane containing the transition states. The trajectories of the two individual strands of the duplex are very similar and not distinguishable at the resolution presented.

Research paper thumbnail of The torsion angle variables of the dinucleotide backbone fragment included in the PCA (see )

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved The conformation of the sugar–phosphate backbone is conventionally defined by six torsion angles labelled α to γ, with χ describing the N-C1′ glycosyl linkage to the bases. For each sugar, there are five torsion angles ν to ν in the furanose ring [conventionally described via a pseudorotation phase angle ()].

Research paper thumbnail of Total potential energy slices in the principal conformational plane spanned by PC1 and PC2 for a GC dinucleotide monophosphate fragment using a radius-dependent dielectric model (RDIE) for the electrostatic term of the potential energy function

<b>Copyright information:</b>Taken from "The physical determinants of the DNA co... more <b>Copyright information:</b>Taken from "The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA"Nucleic Acids Research 2005;33(18):5749-5762.Published online 7 Oct 2005PMCID:PMC1253833.© The Author 2005. Published by Oxford University Press. All rights reserved Low energy regions are labelled from 1 to 6 on the lowest energy slice.

Research paper thumbnail of CES Winter School 2020. 'Sustainable development, complexity and change: thinking and practices for the SDG and other objectives'. Descriptive and evaluation summary report

Research paper thumbnail of (Gardening) Gardening: A Relational Framework for Complex Thinking About Complex Systems

For positive outcomes to be achieved in the management of change in complex systems, our modes of... more For positive outcomes to be achieved in the management of change in complex systems, our modes of thinking need to be congruent with the complexity of the targeted systems. In this chapter, we draw inspiration from the concept of gardening, conceived as a systemic activity of managing relations or the process by which a gardener relates to the relations of a complex system, to develop a relational thinking framework for complex thinking applied to change in complex systems. This framework is based on a relational worldview of interventions, as systemic activities aimed at change in complex systems. We propose a heuristic, in the form of a recursive relational thinking method, which can be used to explore different configurations of relations that represent abstract entities within a modelworld. Further we suggest that these configurations of relations can be the base for a corresponding storyworld, to assist in the narration of change in complex systems. We present this general abst...

Research paper thumbnail of Discussion and Comment (Time Will Tell)

Richard Walsh, Leo Caves, Ana Teixeira de Melo, Susan Stepney, and Emma Uprichard in discussion o... more Richard Walsh, Leo Caves, Ana Teixeira de Melo, Susan Stepney, and Emma Uprichard in discussion on an earlier version of “Time Will Tell: Narrative Expressions of Time in a Complex World”

Research paper thumbnail of Ching, Y. H. et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nature Genet. 37, 423-428

Research paper thumbnail of Automatic Design of Scheduling Policies for Dynamic Multi-objective Job Shop Scheduling via Cooperative Coevolution Genetic Programming..................................................... S. Nguyen, M. Zhang, M. Johnston, and K. Chen Tan 193 An Improved Differential Evolution Algorithm for Pract...

Research paper thumbnail of Stem Cell Reports

Research paper thumbnail of MBO (N) D-A new multibody dynamics methodology for the modeling of macromolecules as substructures

Research paper thumbnail of Special issue on the frontiers of natural computing

Natural Computing, 2013

ABSTRACT This paper extends a recent abstract, tunable model of genomic structural change within ... more ABSTRACT This paper extends a recent abstract, tunable model of genomic structural change within the cell lifecycle and explores its use with simulated evolution. A Boolean model of genetic regulatory networks has been presented to include changes in structure ...

Research paper thumbnail of Building Foundations for Complex Thinking: A call for inter/transdisciplinary collaborations

Research paper thumbnail of Pathways towards knowledge integration: orchestrating interventions in the inter/transdisciplinary ecosystem

Different forms of knowledge and practices of knowing operate at different levels of organisation... more Different forms of knowledge and practices of knowing operate at different levels of organisation within society. Scientific knowledge is but one form of knowing, but its development under a culture of disciplinisation and increasing specialisation has led to its fragmentation and blinded science to the possibilities offered by the integration of knowledge. Humanity's biggest challenges call for organised collective action, informed by the most complex forms of thinking. Interdisciplinarity and transdisciplinarity are privileged routes for rich knowledge construction and integration. There is a pressing need for efforts directed toward the intentional construction of a culture where interdisciplinary and, transdisciplinary practices may flourish. However, we believe significant change will only occur through the orchestration of a set of activities that attend to the complexity of knowledge construction and integration as emergent outcomes of a complex network of processes and r...