A vital part of PIPAC’s package of services is basic and applied research conducted independently or in cooperation with client companies.
Institute Personnel and their Research Interests
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Armando Victor M. Guidote, Jr., Ph.D.
Research Interests:
Organic Chemistry, Natural Products, Chemistry Education
Click here to see the list of his publications.
Armando Jerome H. de Jesus, Jr., Ph.D.
Research Interests:
Molecular dynamics simulations, Membrane-protein interactions, Membrane protein-small molecule interactions
Click here to see the list of his publications.
Ronaldo M. Fabicon, Ph.D.
Research Interests:
Industrial Chemistry
Click here to see the list of his publications.
Crisanto M. Lopez, Dr.rer.nat
Research Interests:
Infection Biology, Fungal Biotechnology
Click here to see the list of his publications.
Giselle Grace F. Lim-Co Yu Kang, Ph.D
Research Interests:
Biochemistry, Enzymes, Analytical Chemistry
Click here to see the list of her publications.
Gilbert U. Yu, D.Eng
Research Interests:
Materials Science (Polymers and Supramolecules), Chemical Education, Development of Lab Experiment Modules
Click here to see the list of his publications.
Ian Ken D. Dimzon, Ph.D
Research Interests:
Applied Analytical Chemistry, Mass Spectrometry, Chemical Metrology
Click here to see the list of his publications.
Anna Carissa M. San Esteban, Ph.D
Research Interests:
Electrochemistry (corrosion, electrocatalytic processes); Coordination Chemistry (coordination polymers, metal-organic frameworks)
Click here to see the list of her publications.
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Selected Publications
2017
Armando J. de Jesus; Hang Yin
Computational Design of Membrane Curvature-Sensing Peptides Book Chapter
In: Samish, Ilan (Ed.): vol. 1529, pp. 417-437, Humana Press, New York, NY, 2017, ISBN: 978-1-4939-6637-0.
Abstract | Links | Tags: CHARMM, curvature-sensing peptides, membrane curvature, molecular dynamics, protein–lipid interactions
@inbook{deJesus2017,
title = {Computational Design of Membrane Curvature-Sensing Peptides},
author = {Armando J. de Jesus and Hang Yin},
editor = {Ilan Samish},
url = {https://link.springer.com/protocol/10.1007%2F978-1-4939-6637-0_22},
doi = {10.1007/978-1-4939-6637-0_22},
isbn = {978-1-4939-6637-0},
year = {2017},
date = {2017-01-01},
journal = {Computational Protein Design},
volume = {1529},
pages = {417-437},
publisher = {Humana Press, New York, NY},
series = {Methods in Molecular Biology},
abstract = {Computer simulations have become an indispensable tool in studying molecular biological systems. The unmatched spatial and temporal resolution that it offers enables for microscopic-level views into the dynamics and mechanics of biological systems. Recent advances in hardware resources have also opened up to computer simulations the investigation of longer timescale biological processes and larger systems. The study of membrane proteins or peptides especially benefits from simulations due to difficulties related to crystallization of such proteins in a membrane environment. In this chapter, we outline the method of molecular dynamics and how it is applied to simulations that involve a peptide and lipid bilayers. In particular, the simulation of a membrane-curvature sensing peptide is examined, and ways of employing computational simulations to design such peptides are discussed.},
keywords = {CHARMM, curvature-sensing peptides, membrane curvature, molecular dynamics, protein–lipid interactions},
pubstate = {published},
tppubtype = {inbook}
}
Computer simulations have become an indispensable tool in studying molecular biological systems. The unmatched spatial and temporal resolution that it offers enables for microscopic-level views into the dynamics and mechanics of biological systems. Recent advances in hardware resources have also opened up to computer simulations the investigation of longer timescale biological processes and larger systems. The study of membrane proteins or peptides especially benefits from simulations due to difficulties related to crystallization of such proteins in a membrane environment. In this chapter, we outline the method of molecular dynamics and how it is applied to simulations that involve a peptide and lipid bilayers. In particular, the simulation of a membrane-curvature sensing peptide is examined, and ways of employing computational simulations to design such peptides are discussed.
2016
Armando J. de Jesus; Ormacinda R. White; Aaron D. Flynn; Hang Yin
Determinants of Curvature-Sensing Behavior for MARCKS-Fragment Peptides Journal Article
In: Biophysical Journal, vol. 110, no. 9, pp. 1980-1992, 2016.
@article{deJesus2016,
title = {Determinants of Curvature-Sensing Behavior for MARCKS-Fragment Peptides},
author = {Armando J. de Jesus and Ormacinda R. White and Aaron D. Flynn and Hang Yin},
url = {https://www.cell.com/biophysj/fulltext/S0006-3495(16)30168-0},
doi = {10.1016/j.bpj.2016.04.007},
year = {2016},
date = {2016-05-10},
journal = {Biophysical Journal},
volume = {110},
number = {9},
pages = {1980-1992},
abstract = {It is increasingly recognized that membrane curvature plays an important role in various cellular activities such as signaling and trafficking, as well as key issues involving health and disease development. Thus, curvature-sensing peptides are essential to the study and detection of highly curved bilayer structures. The effector domain of myristoylated alanine-rich C-kinase substrate (MARCKS-ED) has been demonstrated to have curvature-sensing ability. Research of the MARCKS-ED has further revealed that its Lys and Phe residues play an essential role in how MARCKS-ED detects and binds to curved bilayers. MARCKS-ED has the added property of being a lower-molecular-weight curvature sensor, which offers advantages in production. With that in mind, this work investigates peptide-sequence-related factors that influence curvature sensing and explores whether peptide fragments of even shorter length can function as curvature sensors. Using both experimental and computational methods, we studied the curvature-sensing capabilities of seven fragments of MARCKS-ED. Two of the longer fragments were designed from approximately the two halves of the full-length peptide whereas the five shorter fragments were taken from the central stretch of MARCKS-ED. Fully atomistic molecular dynamics simulations show that the fragments that remain bound to the bilayer exhibit interactions with the bilayer similar to that of the full-length MARCKS-ED peptide. Fluorescence enhancement and anisotropy assays, meanwhile, reveal that five of the MARCKS fragments possess the ability to sense membrane curvature. Based on the sequences of the curvature-sensing fragments, it appears that the ability to sense curvature involves a balance between the numbers of positively charged residues and hydrophobic anchoring residues. Together, these findings help crystallize our understanding of the molecular mechanisms underpinning the curvature-sensing behaviors of peptides, which will prove useful in the design of future curvature sensors.},
keywords = {-},
pubstate = {published},
tppubtype = {article}
}
It is increasingly recognized that membrane curvature plays an important role in various cellular activities such as signaling and trafficking, as well as key issues involving health and disease development. Thus, curvature-sensing peptides are essential to the study and detection of highly curved bilayer structures. The effector domain of myristoylated alanine-rich C-kinase substrate (MARCKS-ED) has been demonstrated to have curvature-sensing ability. Research of the MARCKS-ED has further revealed that its Lys and Phe residues play an essential role in how MARCKS-ED detects and binds to curved bilayers. MARCKS-ED has the added property of being a lower-molecular-weight curvature sensor, which offers advantages in production. With that in mind, this work investigates peptide-sequence-related factors that influence curvature sensing and explores whether peptide fragments of even shorter length can function as curvature sensors. Using both experimental and computational methods, we studied the curvature-sensing capabilities of seven fragments of MARCKS-ED. Two of the longer fragments were designed from approximately the two halves of the full-length peptide whereas the five shorter fragments were taken from the central stretch of MARCKS-ED. Fully atomistic molecular dynamics simulations show that the fragments that remain bound to the bilayer exhibit interactions with the bilayer similar to that of the full-length MARCKS-ED peptide. Fluorescence enhancement and anisotropy assays, meanwhile, reveal that five of the MARCKS fragments possess the ability to sense membrane curvature. Based on the sequences of the curvature-sensing fragments, it appears that the ability to sense curvature involves a balance between the numbers of positively charged residues and hydrophobic anchoring residues. Together, these findings help crystallize our understanding of the molecular mechanisms underpinning the curvature-sensing behaviors of peptides, which will prove useful in the design of future curvature sensors.
2015
Tingliang Wang; Armando J. de Jesus; Yigong Shi; Hang Yin
Pyridoxamine is a substrate of the energy-coupling factor transporter HmpT Journal Article
In: Cell Discovery, vol. 1, pp. 15014, 2015.
Abstract | Links | Tags: ECF transporters, gating mechanism, HmpT, mass spectrometry, molecular dynamics, S-component
@article{Wang2015,
title = {Pyridoxamine is a substrate of the energy-coupling factor transporter HmpT},
author = {Tingliang Wang and Armando J. de Jesus and Yigong Shi and Hang Yin},
url = {https://www.nature.com/articles/celldisc201514},
doi = {10.1038/celldisc.2015.14},
year = {2015},
date = {2015-07-14},
journal = {Cell Discovery},
volume = {1},
pages = {15014},
abstract = {Energy-coupling factor (ECF) transporters belong to a novel family of proteins that forms a subset within the ATP-binding cassette (ABC) transporter family. These proteins are responsible for the uptake of micronutrients in bacteria. ECF transporters are composed of four proteins: the A- and A′-components, the T-component and the S-component. One of the ECF transporters, named HmpT, was crystallized in the apo form with all four components. It is currently unknown whether HmpT serves as a transporter for hydroxymethyl pyrimidine or the different forms of vitamin B6 (pyridoxine, pyridoxal or pyridoxamine). Using a combination of molecular dynamics (MD) simulations and mass spectrometry, we have identified pyridoxamine to be the preferred substrate of HmpT. Mass spectra show that the mass of the substrate from the HmpT–substrate complex matches that of pyridoxamine. MD simulations likewise indicate that pyridoxamine interacts most strongly with most of the conserved residues of the S-component (Glu 41, His 84 and Gln 43) compared with the other vitamin B6 forms. Furthermore, the simulations have implied that loops 1 and 5 of the S-component can participate in the gating action for HmpT.},
keywords = {ECF transporters, gating mechanism, HmpT, mass spectrometry, molecular dynamics, S-component},
pubstate = {published},
tppubtype = {article}
}
Energy-coupling factor (ECF) transporters belong to a novel family of proteins that forms a subset within the ATP-binding cassette (ABC) transporter family. These proteins are responsible for the uptake of micronutrients in bacteria. ECF transporters are composed of four proteins: the A- and A′-components, the T-component and the S-component. One of the ECF transporters, named HmpT, was crystallized in the apo form with all four components. It is currently unknown whether HmpT serves as a transporter for hydroxymethyl pyrimidine or the different forms of vitamin B6 (pyridoxine, pyridoxal or pyridoxamine). Using a combination of molecular dynamics (MD) simulations and mass spectrometry, we have identified pyridoxamine to be the preferred substrate of HmpT. Mass spectra show that the mass of the substrate from the HmpT–substrate complex matches that of pyridoxamine. MD simulations likewise indicate that pyridoxamine interacts most strongly with most of the conserved residues of the S-component (Glu 41, His 84 and Gln 43) compared with the other vitamin B6 forms. Furthermore, the simulations have implied that loops 1 and 5 of the S-component can participate in the gating action for HmpT.
Lei Yan; Armando J. de Jesus; Ryo Tamura; Victoria Li; Kui Cheng; Hang Yin
Curvature sensing MARCKS-ED peptides bind to membranes in a stereo-independent manner Journal Article
In: Journal of Peptide Science, vol. 21, no. 7, pp. 577-585, 2015.
Abstract | Links | Tags: MARCKS‐ED, membrane curvature, simulation, unnatural peptides
@article{Yan2015,
title = {Curvature sensing MARCKS-ED peptides bind to membranes in a stereo-independent manner},
author = {Lei Yan and Armando J. de Jesus and Ryo Tamura and Victoria Li and Kui Cheng and Hang Yin},
url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/psc.2772},
doi = {10.1002/psc.2772},
year = {2015},
date = {2015-06-22},
journal = {Journal of Peptide Science},
volume = {21},
number = {7},
pages = {577-585},
abstract = {Membrane curvature and lipid composition plays a critical role in interchanging of matter and energy in cells. Peptide curvature sensors are known to activate signaling pathways and promote molecular transport across cell membranes. Recently, the 25‐mer MARCKS‐ED peptide, which is derived from the effector domain of the myristoylated alanine‐rich C kinase substrate protein, has been reported to selectively recognize highly curved membrane surfaces. Our previous studies indicated that the naturally occurring l‐MARCKS‐ED peptide could simultaneously detect both phosphatidylserine and curvature. Here, we demonstrate that d‐MARCKS‐ED, composed by unnatural d‐amino acids, has the same activities as its enantiomer, l‐MARCKS‐ED, as a curvature and lipid sensor. An atomistic molecular dynamics simulation suggests that d‐MARCKS‐ED may change from linear to a boat conformation upon binding to the membrane. Comparable enhancement of fluorescence intensity was observed between d‐ and l‐MARCKS‐ED peptides, indicating similar binding affinities. Meanwhile, circular dichroism spectra of d‐ and l‐MARCKS‐ED are almost symmetrical both in the presence and absence of liposomes. These results suggest similar behavior of artificial d‐ and natural l‐MARCKS‐ED peptides when binding to curved membranes. Our studies may contribute to further understanding of how MARCKS‐ED senses membrane curvature as well as provide a new direction to develop novel membrane curvature probes.},
keywords = {MARCKS‐ED, membrane curvature, simulation, unnatural peptides},
pubstate = {published},
tppubtype = {article}
}
Membrane curvature and lipid composition plays a critical role in interchanging of matter and energy in cells. Peptide curvature sensors are known to activate signaling pathways and promote molecular transport across cell membranes. Recently, the 25‐mer MARCKS‐ED peptide, which is derived from the effector domain of the myristoylated alanine‐rich C kinase substrate protein, has been reported to selectively recognize highly curved membrane surfaces. Our previous studies indicated that the naturally occurring l‐MARCKS‐ED peptide could simultaneously detect both phosphatidylserine and curvature. Here, we demonstrate that d‐MARCKS‐ED, composed by unnatural d‐amino acids, has the same activities as its enantiomer, l‐MARCKS‐ED, as a curvature and lipid sensor. An atomistic molecular dynamics simulation suggests that d‐MARCKS‐ED may change from linear to a boat conformation upon binding to the membrane. Comparable enhancement of fluorescence intensity was observed between d‐ and l‐MARCKS‐ED peptides, indicating similar binding affinities. Meanwhile, circular dichroism spectra of d‐ and l‐MARCKS‐ED are almost symmetrical both in the presence and absence of liposomes. These results suggest similar behavior of artificial d‐ and natural l‐MARCKS‐ED peptides when binding to curved membranes. Our studies may contribute to further understanding of how MARCKS‐ED senses membrane curvature as well as provide a new direction to develop novel membrane curvature probes.
2014
Leslie A. Morton; Ryo Tamura; Armando J. de Jesus; Arianna Espinoza; Hang Yin
Biophysical investigations with MARCKS-ED: dissecting the molecular mechanism of its curvature sensing behaviors Journal Article
In: Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1838, no. 12, pp. 3137-3144, 2014.
Abstract | Links | Tags: curvature sensing, EPR, MARCKS-ED, peptide-lipid interactions
@article{Morton2014,
title = {Biophysical investigations with MARCKS-ED: dissecting the molecular mechanism of its curvature sensing behaviors},
author = {Leslie A. Morton and Ryo Tamura and Armando J. de Jesus and Arianna Espinoza and Hang Yin},
url = {https://www.sciencedirect.com/science/article/pii/S0005273614003150},
doi = {10.1016/j.bbamem.2014.08.027},
year = {2014},
date = {2014-09-06},
journal = {Biochimica et Biophysica Acta (BBA) - Biomembranes},
volume = {1838},
number = {12},
pages = {3137-3144},
abstract = {Curved membranes are a common and important attribute in cells. Protein and peptide curvature sensors are known to activate signaling pathways, initiate vesicle budding, trigger membrane fusion, and facilitate molecular transport across cell membranes. Nonetheless, there is little understanding how these proteins and peptides achieve preferential binding of different membrane curvatures. The current study is to elucidate specific factors required for curvature sensing. As a model system, we employed a recently identified peptide curvature sensor, MARCKS-ED, derived from the effector domain of the myristoylated alanine-rich C kinase substrate protein, for these biophysical investigations. An atomistic molecular dynamics (MD) simulation suggested an important role played by the insertion of the Phe residues within MARCKS-ED. To test these observations from our computational simulations, we performed electron paramagnetic resonance (EPR) studies to determine the insertion depth of MARCKS-ED into differently curved membrane bilayers. Next, studies with varied lipid compositions revealed their influence on curvature sensing by MARCKS-ED, suggesting contributions from membrane fluidity, rigidity, as well as various lipid structures. Finally, we demonstrated that the curvature sensing by MARCKS-ED is configuration independent. In summary, our studies have shed further light to the understanding of how MARCKS-ED differentiates between membrane curvatures, which may be generally applicable to protein curvature sensing behavior.},
keywords = {curvature sensing, EPR, MARCKS-ED, peptide-lipid interactions},
pubstate = {published},
tppubtype = {article}
}
Curved membranes are a common and important attribute in cells. Protein and peptide curvature sensors are known to activate signaling pathways, initiate vesicle budding, trigger membrane fusion, and facilitate molecular transport across cell membranes. Nonetheless, there is little understanding how these proteins and peptides achieve preferential binding of different membrane curvatures. The current study is to elucidate specific factors required for curvature sensing. As a model system, we employed a recently identified peptide curvature sensor, MARCKS-ED, derived from the effector domain of the myristoylated alanine-rich C kinase substrate protein, for these biophysical investigations. An atomistic molecular dynamics (MD) simulation suggested an important role played by the insertion of the Phe residues within MARCKS-ED. To test these observations from our computational simulations, we performed electron paramagnetic resonance (EPR) studies to determine the insertion depth of MARCKS-ED into differently curved membrane bilayers. Next, studies with varied lipid compositions revealed their influence on curvature sensing by MARCKS-ED, suggesting contributions from membrane fluidity, rigidity, as well as various lipid structures. Finally, we demonstrated that the curvature sensing by MARCKS-ED is configuration independent. In summary, our studies have shed further light to the understanding of how MARCKS-ED differentiates between membrane curvatures, which may be generally applicable to protein curvature sensing behavior.
2013
Armando J. de Jesus; Noah Kastelowitz; Hang Yin
Changes in lipid density induce membrane curvature Journal Article
In: RSC Advances, vol. 3, no. 33, pp. 13622-13625, 2013.
@article{deJesus2013,
title = {Changes in lipid density induce membrane curvature},
author = {Armando J. de Jesus and Noah Kastelowitz and Hang Yin},
url = {https://pubs.rsc.org/en/content/articlelanding/2013/RA/c3ra42332h},
doi = {10.1039/C3RA42332H},
year = {2013},
date = {2013-06-18},
journal = {RSC Advances},
volume = {3},
number = {33},
pages = {13622-13625},
abstract = {Highly curved bilayer lipid membranes make up the shell of many intra- and extracellular compartments, including organelles and vesicles. Using all-atom molecular dynamics simulations, we show that increasing the density of lipids in the bilayer membrane can induce the membrane to form a curved shape.},
keywords = {-},
pubstate = {published},
tppubtype = {article}
}
Highly curved bilayer lipid membranes make up the shell of many intra- and extracellular compartments, including organelles and vesicles. Using all-atom molecular dynamics simulations, we show that increasing the density of lipids in the bilayer membrane can induce the membrane to form a curved shape.
2012
Armando J. de Jesus; Toby W. Allen
The determinants of hydrophobic mismatch response for transmembrane helices Journal Article
In: Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1828, no. 2, pp. 851-863, 2012.
Abstract | Links | Tags: free energy, hydrophobic mismatch, membrane protein, molecular dynamics, protein–lipid interactions
@article{deJesus2012,
title = {The determinants of hydrophobic mismatch response for transmembrane helices},
author = {Armando J. de Jesus and Toby W. Allen},
url = {https://www.sciencedirect.com/science/article/pii/S0005273612003252},
doi = {10.1016/j.bbamem.2012.09.012},
year = {2012},
date = {2012-09-17},
journal = {Biochimica et Biophysica Acta (BBA) - Biomembranes},
volume = {1828},
number = {2},
pages = {851-863},
abstract = {Hydrophobic mismatch arises from a difference in the hydrophobic thickness of a lipid membrane and a transmembrane protein segment, and is thought to play an important role in the folding, stability and function of membrane proteins. We have investigated the possible adaptations that lipid bilayers and transmembrane α-helices undergo in response to mismatch, using fully-atomistic molecular dynamics simulations totaling 1.4 μs. We have created 25 different tryptophan-alanine-leucine transmembrane α-helical peptide systems, each composed of a hydrophobic alanine–leucine stretch, flanked by 1–4 tryptophan side chains, as well as the β-helical peptide dimer, gramicidin A. Membrane responses to mismatch include changes in local bilayer thickness and lipid order, varying systematically with peptide length. Adding more flanking tryptophan side chains led to an increase in bilayer thinning for negatively mismatched peptides, though it was also associated with a spreading of the bilayer interface. Peptide tilting, bending and stretching were systematic, with tilting dominating the responses, with values of up to ~ 45° for the most positively mismatched peptides. Peptide responses were modulated by the number of tryptophan side chains due to their anchoring roles and distributions around the helices. Potential of mean force calculations for local membrane thickness changes, helix tilting, bending and stretching revealed that membrane deformation is the least energetically costly of all mismatch responses, except for positively mismatched peptides where helix tilting also contributes substantially. This comparison of energetic driving forces of mismatch responses allows for deeper insight into protein stability and conformational changes in lipid membranes.},
keywords = {free energy, hydrophobic mismatch, membrane protein, molecular dynamics, protein–lipid interactions},
pubstate = {published},
tppubtype = {article}
}
Hydrophobic mismatch arises from a difference in the hydrophobic thickness of a lipid membrane and a transmembrane protein segment, and is thought to play an important role in the folding, stability and function of membrane proteins. We have investigated the possible adaptations that lipid bilayers and transmembrane α-helices undergo in response to mismatch, using fully-atomistic molecular dynamics simulations totaling 1.4 μs. We have created 25 different tryptophan-alanine-leucine transmembrane α-helical peptide systems, each composed of a hydrophobic alanine–leucine stretch, flanked by 1–4 tryptophan side chains, as well as the β-helical peptide dimer, gramicidin A. Membrane responses to mismatch include changes in local bilayer thickness and lipid order, varying systematically with peptide length. Adding more flanking tryptophan side chains led to an increase in bilayer thinning for negatively mismatched peptides, though it was also associated with a spreading of the bilayer interface. Peptide tilting, bending and stretching were systematic, with tilting dominating the responses, with values of up to ~ 45° for the most positively mismatched peptides. Peptide responses were modulated by the number of tryptophan side chains due to their anchoring roles and distributions around the helices. Potential of mean force calculations for local membrane thickness changes, helix tilting, bending and stretching revealed that membrane deformation is the least energetically costly of all mismatch responses, except for positively mismatched peptides where helix tilting also contributes substantially. This comparison of energetic driving forces of mismatch responses allows for deeper insight into protein stability and conformational changes in lipid membranes.
Armando J. de Jesus; Toby W. Allen
The role of tryptophan side chains in membrane protein anchoring and hydrophobic mismatch Journal Article
In: Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1828, no. 2, pp. 864-876, 2012.
Abstract | Links | Tags: free energy, hydrophobic mismatch, membrane protein, molecular dynamics, protein–lipid interactions, tryptophan
@article{deJesus2012b,
title = {The role of tryptophan side chains in membrane protein anchoring and hydrophobic mismatch},
author = {Armando J. de Jesus and Toby W. Allen},
url = {https://www.sciencedirect.com/science/article/pii/S0005273612003227},
doi = {10.1016/j.bbamem.2012.09.009},
year = {2012},
date = {2012-09-16},
journal = {Biochimica et Biophysica Acta (BBA) - Biomembranes},
volume = {1828},
number = {2},
pages = {864-876},
abstract = {Tryptophan (Trp) is abundant in membrane proteins, preferentially residing near the lipid–water interface where it is thought to play a significant anchoring role. Using a total of 3 μs of molecular dynamics simulations for a library of hydrophobic WALP-like peptides, a long poly-Leu α-helix, and the methyl-indole analog, we explore the thermodynamics of the Trp movement in membranes that governs the stability and orientation of transmembrane protein segments. We examine the dominant hydrogen-bonding interactions between the Trp and lipid carbonyl and phosphate moieties, cation–π interactions to lipid choline moieties, and elucidate the contributions to the thermodynamics that serve to localize the Trp, by ~ 4 kcal/mol, near the membrane glycerol backbone region. We show a striking similarity between the free energy to move an isolated Trp side chain to that found from a wide range of WALP peptides, suggesting that the location of this side chain is nearly independent of the host transmembrane segment. Our calculations provide quantitative measures that explain Trp's role as a modulator of responses to hydrophobic mismatch, providing a deeper understanding of how lipid composition may control a range of membrane active peptides and proteins.},
keywords = {free energy, hydrophobic mismatch, membrane protein, molecular dynamics, protein–lipid interactions, tryptophan},
pubstate = {published},
tppubtype = {article}
}
Tryptophan (Trp) is abundant in membrane proteins, preferentially residing near the lipid–water interface where it is thought to play a significant anchoring role. Using a total of 3 μs of molecular dynamics simulations for a library of hydrophobic WALP-like peptides, a long poly-Leu α-helix, and the methyl-indole analog, we explore the thermodynamics of the Trp movement in membranes that governs the stability and orientation of transmembrane protein segments. We examine the dominant hydrogen-bonding interactions between the Trp and lipid carbonyl and phosphate moieties, cation–π interactions to lipid choline moieties, and elucidate the contributions to the thermodynamics that serve to localize the Trp, by ~ 4 kcal/mol, near the membrane glycerol backbone region. We show a striking similarity between the free energy to move an isolated Trp side chain to that found from a wide range of WALP peptides, suggesting that the location of this side chain is nearly independent of the host transmembrane segment. Our calculations provide quantitative measures that explain Trp's role as a modulator of responses to hydrophobic mismatch, providing a deeper understanding of how lipid composition may control a range of membrane active peptides and proteins.
Xiaohui Wang; Lisa C. Loram; Khara Ramos; Armando J. de Jesus; Jacob Thomas; Kui Cheng; Anireddy Reddy; Andrew A. Somogyi; Mark R. Hutchinson; Linda R. Watkins; Hang Yin
Morphine activates neuroinflammation in a manner parallel to endotoxin Journal Article
In: Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 16, pp. 6325-6330, 2012.
Abstract | Links | Tags: drug discovery, pain management therapy, protein–protein interaction
@article{Wang2012,
title = {Morphine activates neuroinflammation in a manner parallel to endotoxin},
author = {Xiaohui Wang and Lisa C. Loram and Khara Ramos and Armando J. de Jesus and Jacob Thomas and Kui Cheng and Anireddy Reddy and Andrew A. Somogyi and Mark R. Hutchinson and Linda R. Watkins and Hang Yin},
url = {https://www.pnas.org/content/109/16/6325.long},
doi = {10.1073/pnas.1200130109},
year = {2012},
date = {2012-04-17},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {109},
number = {16},
pages = {6325-6330},
abstract = {Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.},
keywords = {drug discovery, pain management therapy, protein–protein interaction},
pubstate = {published},
tppubtype = {article}
}
Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.