Riccardo Baron - Profile on Academia.edu (original) (raw)
Papers by Riccardo Baron
Coarse-Graining of TIP4P/2005, TIP4P-Ew, SPC/E, and TIP3P to Monatomic Anisotropic Water Models Using Relative Entropy Minimization
Journal of Chemical Theory and Computation, 2014
ABSTRACT Coarse-grained models of are becoming a competitive alternative for modeling processes t... more ABSTRACT Coarse-grained models of are becoming a competitive alternative for modeling processes that occur over time and length scales beyond the reach of fully atomistic molecular simulations. Ideally, coarse-grained models should not only achieve high computational efficiency, but also provide accurate predictions and fundamental insight into the role of molecular interactions the characteristic behavior and properties of the system they model. In this work we derive a series of monatomic coarse-grained water models mXREM from the most popular atomistic water models X = TIP3P, SPC/E, TIP4P-Ew and TIP4P/2005, using the relative entropy minimization (REM) method. Each coarse-grained water molecule is represented by a single particle that interacts through short-ranged anisotropic interactions that encourage the formation of “hydrogen-bonded” structures. We systematically investigate the features of the coarse-grained models in reproducing over twenty structural, dynamic and thermodynamic properties of the reference atomistic water models – including the existence and locus of the characteristic density anomaly. The mXREM coarse-grained models reproduce quite faithfully the radial and angular distribution function of water, produce a temperature of maximum density (TMD) and stabilize the ice I crystal. Moreover, the ratio between the TMD and the melting temperature of the crystal in the mXREM models and liquid-ice equilibrium properties show reasonable agreement with the results of the corresponding atomistic models. The mXREM models, however, severely underestimate the cohesive energy of the condensed water phases. We investigate which specific limitations of the coarse-grained models arise from the REM methodology, from the monatomic nature of the models, and from the Stillinger-Weber interaction potential form. Our analysis indicates that a small compromise in the accuracy of structural properties can result in a significant increase of the overall accuracy and representability of the coarse-grained water models. We evaluate the accuracy of the atomistic and the monatomic anisotropic coarse-grained water models, including the mW water model, in reproducing experimental water properties. We find that mW and mTIP4P/2005REM score closer to experiment than widely used atomistic water models. We conclude that monatomic models of water with short-range, anisotropic “hydrogen-bonding” three-body interactions can be competitive in accuracy with fully atomistic models for the study of a wide range of properties and phenomena at less than 1/100th of the computational cost.
LSD1/CoREST - H3-Histone Molecular Recognition: Inter-Domain Motions in an Allosteric Nanoscale Clamp Revealed by Computer Simulations
Biophysical Journal, 2014
A Complete Configurational Ensemble Approach to Expand Lsd1/Corest Druggability
Biophysical Journal, 2014
Molecular dynamics simulations indicate an induced-fit mechanism for LSD1/CoREST-H3-histone molecular recognition
BMC biophysics, 2013
Lysine Specific Demethylase (LSD1 or KDM1A) in complex with its co-repressor protein CoREST catal... more Lysine Specific Demethylase (LSD1 or KDM1A) in complex with its co-repressor protein CoREST catalyzes the demethylation of the H3 histone N-terminal tail and is currently one of the most promising epigenetic targets for drug discovery against cancer and neurodegenerative diseases. Models of non-covalent binding, such as lock and key, induced-fit, and conformational selection could help explaining the molecular mechanism of LSD1/CoREST-H3-histone association, thus guiding drug discovery and design efforts. Here, we quantify the extent to which LSD1/CoREST substrate binding is consistent with these hypothetical models using LSD1/CoREST conformational ensembles obtained through extensive explicit solvent molecular dynamics (MD) simulations. We find that an induced-fit model is the most representative of LSD1/CoREST-H3-histone non-covalent binding and accounts for the local conformational changes occurring in the H3-histone binding site. We also show that conformational selection - desp...
Comparison of atomic-level and coarse-grained models for liquid hydrocarbons from molecular dynamics configurational entropy estimates
The journal of physical chemistry. B, Jan 27, 2006
Molecular liquids can be modeled at different levels of spatial resolution. In atomic-level (AL) ... more Molecular liquids can be modeled at different levels of spatial resolution. In atomic-level (AL) models, all (heavy) atoms can be explicitly simulated. In coarse-grained (CG) models, particles (beads) that represent groups of covalently bound atoms are used as elementary units. Ideally, a CG model should reproduce the thermodynamic and structural properties of the corresponding AL model after mapping to the lower-resolution scale. In the present work, two such models are investigated: (i) the classical GROMOS atomic-level model; (ii) a CG model recently proposed by Marrink et al., which maps approximately four non-hydrogen atoms to one bead [J. Phys. Chem. B 2004, 108, 750]. The study is restricted to n-alkanes whose aliphatic fragments are abundantly found in lipids of biological interest. Additionally, cis-9-octadecene is included, as a template chain of the lipid dioleoylphosphatidylcholine (DOPC). The two representations of molecules in the liquid phase are compared in terms of ...
Angewandte Chemie (International ed. in English), Jan 6, 2004
The folding of a polypeptide chain into the stable threedimensional structure of a biologically a... more The folding of a polypeptide chain into the stable threedimensional structure of a biologically active protein is still not understood in atomic detail. However, several research groups have recently reported successful atomistic simulations of secondary-structure formation, including the formation of helices of different types, b turns and b sheets of a-and b-peptides. Insight into the nature of both the folding process and the unfolded state has been obtained from various studies simulating the reversible folding of peptides. This development is encouraging and indicates that the biomolecular force fields in use are approaching the accuracy required to predict folding equilibria, although this has so far been demonstrated only for short polypeptides.
A marine analgesic peptide, Contulakin-G, and neurotensin are distinct agonists for neurotensin receptors: uncovering structural determinants of desensitization properties
Frontiers in pharmacology, 2015
Neurotensin receptors have been studied as molecular targets for the treatment of pain, schizophr... more Neurotensin receptors have been studied as molecular targets for the treatment of pain, schizophrenia, addiction, or cancer. Neurotensin (NT) and Contulakin-G, a glycopeptide isolated from a predatory cone snail Conus geographus, share a sequence similarity at the C-terminus, which is critical for activation of neurotensin receptors. Both peptides are potent analgesics, although affinity and agonist potency of Contulakin-G toward neurotensin receptors are significantly lower, as compared to those for NT. In this work, we show that the weaker agonist properties of Contulakin-G result in inducing significantly less desensitization of neurotensin receptors and preserving their cell-surface density. Structure-activity relationship (SAR) studies suggested that both glycosylation and charged amino acid residues in Contulakin-G or NT played important roles in desensitizing neurotensin receptors. Computational modeling studies of human neurotensin receptor NTS1 and Contulakin-G confirmed th...
Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia
Leukemia, 2015
Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor... more Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays est...
Simulation of an Intrinisically Disordered Protein
COMP Emilio Esposito, Scott Wildman Tuesday, March 27, 2012
in computer-aided drug design
PHYS 534-Solvation structure and dynamics of aqueous L-glutamic acid
A combined computational and biochemical analysis of oxygen diffusion and reactivity in a flavoprotein monooxygenase and oxidase
Following biomolecular recognition and association at the microsecond/atomic scale
Multiple pathways guide oxygen diffusion in flavoenzymes
When water-mediated becomes water-driven: Cavity-ligand binding with explicit, coarse-grained solvent
Molecular recognition and epigenetic modulation: The LSD1-CoREST nanoscale clamp prototype system
Coarse-Graining of TIP4P/2005, TIP4P-Ew, SPC/E, and TIP3P to Monatomic Anisotropic Water Models Using Relative Entropy Minimization
Journal of Chemical Theory and Computation, 2014
ABSTRACT Coarse-grained models of are becoming a competitive alternative for modeling processes t... more ABSTRACT Coarse-grained models of are becoming a competitive alternative for modeling processes that occur over time and length scales beyond the reach of fully atomistic molecular simulations. Ideally, coarse-grained models should not only achieve high computational efficiency, but also provide accurate predictions and fundamental insight into the role of molecular interactions the characteristic behavior and properties of the system they model. In this work we derive a series of monatomic coarse-grained water models mXREM from the most popular atomistic water models X = TIP3P, SPC/E, TIP4P-Ew and TIP4P/2005, using the relative entropy minimization (REM) method. Each coarse-grained water molecule is represented by a single particle that interacts through short-ranged anisotropic interactions that encourage the formation of “hydrogen-bonded” structures. We systematically investigate the features of the coarse-grained models in reproducing over twenty structural, dynamic and thermodynamic properties of the reference atomistic water models – including the existence and locus of the characteristic density anomaly. The mXREM coarse-grained models reproduce quite faithfully the radial and angular distribution function of water, produce a temperature of maximum density (TMD) and stabilize the ice I crystal. Moreover, the ratio between the TMD and the melting temperature of the crystal in the mXREM models and liquid-ice equilibrium properties show reasonable agreement with the results of the corresponding atomistic models. The mXREM models, however, severely underestimate the cohesive energy of the condensed water phases. We investigate which specific limitations of the coarse-grained models arise from the REM methodology, from the monatomic nature of the models, and from the Stillinger-Weber interaction potential form. Our analysis indicates that a small compromise in the accuracy of structural properties can result in a significant increase of the overall accuracy and representability of the coarse-grained water models. We evaluate the accuracy of the atomistic and the monatomic anisotropic coarse-grained water models, including the mW water model, in reproducing experimental water properties. We find that mW and mTIP4P/2005REM score closer to experiment than widely used atomistic water models. We conclude that monatomic models of water with short-range, anisotropic “hydrogen-bonding” three-body interactions can be competitive in accuracy with fully atomistic models for the study of a wide range of properties and phenomena at less than 1/100th of the computational cost.
LSD1/CoREST - H3-Histone Molecular Recognition: Inter-Domain Motions in an Allosteric Nanoscale Clamp Revealed by Computer Simulations
Biophysical Journal, 2014
A Complete Configurational Ensemble Approach to Expand Lsd1/Corest Druggability
Biophysical Journal, 2014
Molecular dynamics simulations indicate an induced-fit mechanism for LSD1/CoREST-H3-histone molecular recognition
BMC biophysics, 2013
Lysine Specific Demethylase (LSD1 or KDM1A) in complex with its co-repressor protein CoREST catal... more Lysine Specific Demethylase (LSD1 or KDM1A) in complex with its co-repressor protein CoREST catalyzes the demethylation of the H3 histone N-terminal tail and is currently one of the most promising epigenetic targets for drug discovery against cancer and neurodegenerative diseases. Models of non-covalent binding, such as lock and key, induced-fit, and conformational selection could help explaining the molecular mechanism of LSD1/CoREST-H3-histone association, thus guiding drug discovery and design efforts. Here, we quantify the extent to which LSD1/CoREST substrate binding is consistent with these hypothetical models using LSD1/CoREST conformational ensembles obtained through extensive explicit solvent molecular dynamics (MD) simulations. We find that an induced-fit model is the most representative of LSD1/CoREST-H3-histone non-covalent binding and accounts for the local conformational changes occurring in the H3-histone binding site. We also show that conformational selection - desp...
Comparison of atomic-level and coarse-grained models for liquid hydrocarbons from molecular dynamics configurational entropy estimates
The journal of physical chemistry. B, Jan 27, 2006
Molecular liquids can be modeled at different levels of spatial resolution. In atomic-level (AL) ... more Molecular liquids can be modeled at different levels of spatial resolution. In atomic-level (AL) models, all (heavy) atoms can be explicitly simulated. In coarse-grained (CG) models, particles (beads) that represent groups of covalently bound atoms are used as elementary units. Ideally, a CG model should reproduce the thermodynamic and structural properties of the corresponding AL model after mapping to the lower-resolution scale. In the present work, two such models are investigated: (i) the classical GROMOS atomic-level model; (ii) a CG model recently proposed by Marrink et al., which maps approximately four non-hydrogen atoms to one bead [J. Phys. Chem. B 2004, 108, 750]. The study is restricted to n-alkanes whose aliphatic fragments are abundantly found in lipids of biological interest. Additionally, cis-9-octadecene is included, as a template chain of the lipid dioleoylphosphatidylcholine (DOPC). The two representations of molecules in the liquid phase are compared in terms of ...
Angewandte Chemie (International ed. in English), Jan 6, 2004
The folding of a polypeptide chain into the stable threedimensional structure of a biologically a... more The folding of a polypeptide chain into the stable threedimensional structure of a biologically active protein is still not understood in atomic detail. However, several research groups have recently reported successful atomistic simulations of secondary-structure formation, including the formation of helices of different types, b turns and b sheets of a-and b-peptides. Insight into the nature of both the folding process and the unfolded state has been obtained from various studies simulating the reversible folding of peptides. This development is encouraging and indicates that the biomolecular force fields in use are approaching the accuracy required to predict folding equilibria, although this has so far been demonstrated only for short polypeptides.
A marine analgesic peptide, Contulakin-G, and neurotensin are distinct agonists for neurotensin receptors: uncovering structural determinants of desensitization properties
Frontiers in pharmacology, 2015
Neurotensin receptors have been studied as molecular targets for the treatment of pain, schizophr... more Neurotensin receptors have been studied as molecular targets for the treatment of pain, schizophrenia, addiction, or cancer. Neurotensin (NT) and Contulakin-G, a glycopeptide isolated from a predatory cone snail Conus geographus, share a sequence similarity at the C-terminus, which is critical for activation of neurotensin receptors. Both peptides are potent analgesics, although affinity and agonist potency of Contulakin-G toward neurotensin receptors are significantly lower, as compared to those for NT. In this work, we show that the weaker agonist properties of Contulakin-G result in inducing significantly less desensitization of neurotensin receptors and preserving their cell-surface density. Structure-activity relationship (SAR) studies suggested that both glycosylation and charged amino acid residues in Contulakin-G or NT played important roles in desensitizing neurotensin receptors. Computational modeling studies of human neurotensin receptor NTS1 and Contulakin-G confirmed th...
Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia
Leukemia, 2015
Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor... more Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays est...
Simulation of an Intrinisically Disordered Protein
COMP Emilio Esposito, Scott Wildman Tuesday, March 27, 2012
in computer-aided drug design
PHYS 534-Solvation structure and dynamics of aqueous L-glutamic acid
A combined computational and biochemical analysis of oxygen diffusion and reactivity in a flavoprotein monooxygenase and oxidase
Following biomolecular recognition and association at the microsecond/atomic scale
Multiple pathways guide oxygen diffusion in flavoenzymes
When water-mediated becomes water-driven: Cavity-ligand binding with explicit, coarse-grained solvent
Molecular recognition and epigenetic modulation: The LSD1-CoREST nanoscale clamp prototype system