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Article ; Online: Dissecting the Interaction Fingerprints and Binding Affinity of BYL719 Analogs Targeting PI3Kα.

Dehghani-Ghahnaviyeh, Sepehr / Soylu, Cihan / Furet, Pascal / Velez-Vega, Camilo

The journal of physical chemistry. B

2024 Volume 128, Issue 8, Page(s) 1819–1829

Abstract: Phosphatidylinositol-3-kinase Alpha (PI3Kα) is a lipid kinase which regulates signaling pathways involved in cell proliferation. Dysregulation of these pathways promotes several human cancers, pushing for the development of anticancer drugs to target ... ...

Abstract	Phosphatidylinositol-3-kinase Alpha (PI3Kα) is a lipid kinase which regulates signaling pathways involved in cell proliferation. Dysregulation of these pathways promotes several human cancers, pushing for the development of anticancer drugs to target PI3Kα. One such medicinal chemistry campaign at Novartis led to the discovery of BYL719 (Piqray, Alpelicib), a PI3Kα inhibitor approved by the FDA in 2019 for treatment of HR+/HER2-advanced breast cancer with a PIK3CA mutation. Structure-based drug design played a key role in compound design and optimization throughout the discovery process. However, further characterization of potency drivers via structural dynamics and energetic analyses can be advantageous for ensuing PI3Kα programs. Here, our goal is to employ various in-silico techniques, including molecular simulations and machine learning, to characterize 14 ligands from the BYL719 analogs and predict their binding affinities. The structural insights from molecular simulations suggest that although the ligand-hinge interaction is the primary driver of ligand stability at the pocket, the R group positioning at C2 or C6 of pyridine/pyrimidine also plays a major role. Binding affinities predicted via thermodynamic integration (TI) are in good agreement with previously reported IC50s. Yet, computationally demanding techniques such as TI might not always be the most efficient approach for affinity prediction, as in our case study, fast high-throughput techniques were capable of classifying compounds as active or inactive, and one docking approach showed accuracy comparable to TI.
MeSH term(s)	Humans ; Female ; Phosphatidylinositol 3-Kinase ; Ligands ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Breast Neoplasms/drug therapy ; Thiazoles
Chemical Substances	Alpelisib (08W5N2C97Q) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Ligands ; Antineoplastic Agents ; Thiazoles
Language	English
Publishing date	2024-02-19
Publishing country	United States
Document type	Journal Article
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.3c06766
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Revealing Molecular Determinants of hERG Blocker and Activator Binding.

Dickson, Callum J / Velez-Vega, Camilo / Duca, Jose S

Journal of chemical information and modeling

2020 Volume 60, Issue 1, Page(s) 192–203

Abstract: The Kv11.1 potassium channel, encoded by the human ether-a-go-go-related gene (hERG), plays an essential role in the cardiac action potential. hERG blockade by small molecules can induce "torsade de pointes" arrhythmias and sudden death; as such, it is ... ...

Abstract	The Kv11.1 potassium channel, encoded by the human ether-a-go-go-related gene (hERG), plays an essential role in the cardiac action potential. hERG blockade by small molecules can induce "torsade de pointes" arrhythmias and sudden death; as such, it is an important off-target to avoid during drug discovery. Recently, a cryo-EM structure of the open channel state of hERG was reported, opening the door to in silico docking analyses and interpretation of hERG structure-activity relationships, with a view to avoiding blocking activity. Despite this, docking directly to this cryo-EM structure has been reported to yield binding modes that are unable to explain known mutagenesis data. In this work, we use molecular dynamics simulations to sample a range of channel conformations and run ensemble docking campaigns at the known hERG binding site below the selectivity filter, composed of the central cavity and the four deep hydrophobic pockets. We identify a hERG conformational state allowing discrimination of blockers vs nonblockers from docking; furthermore, the binding pocket agrees with mutagenesis data, and blocker binding modes fit the hERG blocker pharmacophore. We then use the same protocol to identify a binding pocket in the hERG channel pore for hERG activators, again agreeing with the reported mutagenesis. Our approach may be useful in drug discovery campaigns to prioritize candidate compounds based on hERG liability via virtual docking screens.
MeSH term(s)	Binding Sites ; Cryoelectron Microscopy ; Datasets as Topic ; ERG1 Potassium Channel/agonists ; ERG1 Potassium Channel/antagonists & inhibitors ; ERG1 Potassium Channel/chemistry ; HEK293 Cells ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Patch-Clamp Techniques ; Protein Conformation ; Solvents/chemistry
Chemical Substances	ERG1 Potassium Channel ; KCNH2 protein, human ; Solvents
Language	English
Publishing date	2020-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.9b00773
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Article ; Online: Evaluating the Efficiency of the Martini Force Field to Study Protein Dimerization in Aqueous and Membrane Environments.

Lamprakis, Christos / Andreadelis, Ioannis / Manchester, John / Velez-Vega, Camilo / Duca, José S / Cournia, Zoe

Journal of chemical theory and computation

2021 Volume 17, Issue 5, Page(s) 3088–3102

Abstract: Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ... ...

Abstract	Protein-protein complex assembly is one of the major drivers of biological response. Understanding the mechanisms of protein oligomerization/dimerization would allow one to elucidate how these complexes participate in biological activities and could ultimately lead to new approaches in designing novel therapeutic agents. However, determining the exact association pathways and structures of such complexes remains a challenge. Here, we use parallel tempering metadynamics simulations in the well-tempered ensemble to evaluate the performance of Martini 2.2P and Martini open-beta 3 (Martini 3) force fields in reproducing the structure and energetics of the dimerization process of membrane proteins and proteins in an aqueous solution in reasonable accuracy and throughput. We find that Martini 2.2P systematically overestimates the free energy of association by estimating large barriers in distinct areas, which likely leads to overaggregation when multiple monomers are present. In comparison, the less viscous Martini 3 results in a systematic underestimation of the free energy of association for proteins in solution, while it performs well in describing the association of membrane proteins. In all cases, the near-native dimer complexes are identified as minima in the free energy surface albeit not always as the lowest minima. In the case of Martini 3, we find that the spurious supramolecular protein aggregation present in Martini 2.2P multimer simulations is alleviated and thus this force field may be more suitable for the study of protein oligomerization. We propose that the use of enhanced sampling simulations with a refined coarse-grained force field and appropriately defined collective variables is a robust approach for studying the protein dimerization process, although one should be cautious of the ranking of energy minima.
MeSH term(s)	Cell Membrane/chemistry ; Dimerization ; Protein Multimerization ; Proteins/chemistry ; Thermodynamics ; Water/chemistry
Chemical Substances	Proteins ; Water (059QF0KO0R)
Language	English
Publishing date	2021-04-29
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.0c00507
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Article: Membrane Composition and Raf[CRD]-Membrane Attachment Are Driving Forces for K-Ras4B Dimer Stability

Andreadelis, Ioannis / Kiriakidi, Sofia / Lamprakis, Christos / Theodoropoulou, Anastasia / Doerr, Stefan / Chatzigoulas, Alexios / Manchester, John / Velez-Vega, Camilo / Duca, José S. / Cournia, Zoe

Journal of physical chemistry. 2022 Feb. 10, v. 126, no. 7

2022

Abstract: Ras proteins are membrane-anchored GTPases that regulate key cellular signaling networks. It has been recently shown that different anionic lipid types can affect the properties of Ras in terms of dimerization/clustering on the cell membrane. To ... ...

Abstract	Ras proteins are membrane-anchored GTPases that regulate key cellular signaling networks. It has been recently shown that different anionic lipid types can affect the properties of Ras in terms of dimerization/clustering on the cell membrane. To understand the effects of anionic lipids on key spatiotemporal properties of dimeric K-Ras4B, we perform all-atom molecular dynamics simulations of the dimer K-Ras4B in the presence and absence of Raf[RBD/CRD] effectors on two model anionic lipid membranes: one containing 78% mol DOPC, 20% mol DOPS, and 2% mol PIP2 and another one with enhanced concentration of anionic lipids containing 50% mol DOPC, 40% mol DOPS, and 10% mol PIP2. Analysis of our results unveils the orientational space of dimeric K-Ras4B and shows that the stability of the dimer is enhanced on the membrane containing a high concentration of anionic lipids in the absence of Raf effectors. This enhanced stability is also observed in the presence of Raf[RBD/CRD] effectors although it is not influenced by the concentration of anionic lipids in the membrane, but rather on the ability of Raf[CRD] to anchor to the membrane. We generate dominant K-Ras4B conformations by Markov state modeling and yield the population of states according to the K-Ras4B orientation on the membrane. For the membrane containing anionic lipids, we observe correlations between the diffusion of K-Ras4B and PIP2 and anchoring of anionic lipids to the Raf[CRD] domain. We conclude that the presence of effectors with the Raf[CRD] domain anchoring on the membrane as well as the membrane composition both influence the conformational stability of the K-Ras4B dimer, enabling the preservation of crucial interface interactions.
Keywords	cell membranes ; dimerization ; guanosinetriphosphatase ; lipids ; molecular dynamics
Language	English
Dates of publication	2022-0210
Size	p. 1504-1519.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5207
DOI	10.1021/acs.jpcb.1c01184
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Martini 3 Force Field Parameters for Protein Lipidation Post-Translational Modifications.

Koukos, Panagiotis I / Dehghani-Ghahnaviyeh, Sepehr / Velez-Vega, Camilo / Manchester, John / Tieleman, D Peter / Duca, José S / Souza, Paulo C T / Cournia, Zoe

Journal of chemical theory and computation

2023 Volume 19, Issue 23, Page(s) 8901–8918

Abstract: Protein lipidations are vital co/post-translational modifications that tether lipid tails to specific protein amino acids, allowing them to anchor to biological membranes, switch their subcellular localization, and modulate association with other ... ...

Abstract	Protein lipidations are vital co/post-translational modifications that tether lipid tails to specific protein amino acids, allowing them to anchor to biological membranes, switch their subcellular localization, and modulate association with other proteins. Such lipidations are thus crucial for multiple biological processes including signal transduction, protein trafficking, and membrane localization and are implicated in various diseases as well. Examples of lipid-anchored proteins include the Ras family of proteins that undergo farnesylation; actin and gelsolin that are myristoylated; phospholipase D that is palmitoylated; glycosylphosphatidylinositol-anchored proteins; and others. Here, we develop parameters for cysteine-targeting farnesylation, geranylgeranylation, and palmitoylation, as well as glycine-targeting myristoylation for the latest version of the Martini 3 coarse-grained force field. The parameters are developed using the CHARMM36m all-atom force field parameters as reference. The behavior of the coarse-grained models is consistent with that of the all-atom force field for all lipidations and reproduces key dynamical and structural features of lipid-anchored peptides, such as the solvent-accessible surface area, bilayer penetration depth, and representative conformations of the anchors. The parameters are also validated in simulations of the lipid-anchored peripheral membrane proteins Rheb and Arf1, after comparison with independent all-atom simulations. The parameters, along with mapping schemes for the popular
MeSH term(s)	Lipid Bilayers/chemistry ; Thermodynamics ; Molecular Dynamics Simulation ; Cell Membrane ; Proteins ; Protein Processing, Post-Translational
Chemical Substances	Lipid Bilayers ; Proteins
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.3c00604
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Article ; Online: Membrane Composition and Raf[CRD]-Membrane Attachment Are Driving Forces for K-Ras4B Dimer Stability.

The journal of physical chemistry. B

2022 Volume 126, Issue 7, Page(s) 1504–1519

Abstract	Ras proteins are membrane-anchored GTPases that regulate key cellular signaling networks. It has been recently shown that different anionic lipid types can affect the properties of Ras in terms of dimerization/clustering on the cell membrane. To understand the effects of anionic lipids on key spatiotemporal properties of dimeric K-Ras4B, we perform all-atom molecular dynamics simulations of the dimer K-Ras4B in the presence and absence of Raf[RBD/CRD] effectors on two model anionic lipid membranes: one containing 78% mol DOPC, 20% mol DOPS, and 2% mol PIP2 and another one with enhanced concentration of anionic lipids containing 50% mol DOPC, 40% mol DOPS, and 10% mol PIP2. Analysis of our results unveils the orientational space of dimeric K-Ras4B and shows that the stability of the dimer is enhanced on the membrane containing a high concentration of anionic lipids in the absence of Raf effectors. This enhanced stability is also observed in the presence of Raf[RBD/CRD] effectors although it is not influenced by the concentration of anionic lipids in the membrane, but rather on the ability of Raf[CRD] to anchor to the membrane. We generate dominant K-Ras4B conformations by Markov state modeling and yield the population of states according to the K-Ras4B orientation on the membrane. For the membrane containing anionic lipids, we observe correlations between the diffusion of K-Ras4B and PIP2 and anchoring of anionic lipids to the Raf[CRD] domain. We conclude that the presence of effectors with the Raf[CRD] domain anchoring on the membrane as well as the membrane composition both influence the conformational stability of the K-Ras4B dimer, enabling the preservation of crucial interface interactions.
MeSH term(s)	Lipids ; Molecular Conformation ; Molecular Dynamics Simulation ; Protein Binding ; Proto-Oncogene Proteins p21(ras)/metabolism ; ras Proteins/metabolism
Chemical Substances	Lipids ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2022-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.1c01184
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Article ; Online: N-terminal β-strand in YAP is critical for stronger binding to scalloped relative to TEAD transcription factor.

Bokhovchuk, Fedir / Mesrouze, Yannick / Meyerhofer, Marco / Fontana, Patrizia / Zimmermann, Catherine / Villard, Frédéric / Erdmann, Dirk / Kallen, Joerg / Scheufler, Clemens / Velez-Vega, Camilo / Chène, Patrick

Protein science : a publication of the Protein Society

2022 Volume 32, Issue 1, Page(s) e4545

Abstract: The yes-associated protein (YAP) regulates the transcriptional activity of the TEAD transcription factors that are key in the control of organ morphogenesis. YAP interacts with TEAD via three secondary structure elements: a β-strand, an α-helix, and an Ω- ...

Abstract	The yes-associated protein (YAP) regulates the transcriptional activity of the TEAD transcription factors that are key in the control of organ morphogenesis. YAP interacts with TEAD via three secondary structure elements: a β-strand, an α-helix, and an Ω-loop. Earlier results have shown that the β-strand has only a marginal contribution in the YAP:TEAD interaction, but we show here that it significantly enhances the affinity of YAP for the Drosophila homolog of TEAD, scalloped (Sd). Nuclear magnetic resonance shows that the β-strand adopts a more rigid conformation once bound to Sd; pre-steady state kinetic measurements show that the YAP:Sd complex is more stable. Although the crystal structures of the YAP:TEAD and YAP:Sd complexes reveal no differences at the binding interface that could explain these results. Molecular Dynamics simulations are in line with our experimental findings regarding β-strand stability and overall binding affinity of YAP to TEAD and Sd. In particular, RMSF, correlated motion and MMGBSA analyses suggest that β-sheet fluctuations play a relevant role in YAP
MeSH term(s)	Transcription Factors/chemistry ; TEA Domain Transcription Factors ; DNA-Binding Proteins/chemistry ; Protein Conformation, beta-Strand ; Gene Expression Regulation ; Protein Binding
Chemical Substances	Transcription Factors ; TEA Domain Transcription Factors ; DNA-Binding Proteins
Language	English
Publishing date	2022-12-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4545
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Tilting the balance between canonical and noncanonical conformations for the H1 hypervariable loop of a llama VHH through point mutations.

Mahajan, Sai Pooja / Velez-Vega, Camilo / Escobedo, Fernando A

The journal of physical chemistry. B

2013 Volume 117, Issue 1, Page(s) 13–24

Abstract: Nanobodies are single-domain antibodies found in camelids. These are the smallest naturally occurring binding domains and derive functionality via three hypervariable loops (H1-H3) that form the binding surface. They are excellent candidates for antibody ...

Abstract	Nanobodies are single-domain antibodies found in camelids. These are the smallest naturally occurring binding domains and derive functionality via three hypervariable loops (H1-H3) that form the binding surface. They are excellent candidates for antibody engineering because of their favorable characteristics like small size, high solubility, and stability. To rationally engineer antibodies with affinity for a specific target, the hypervariable loops can be tailored to obtain the desired binding surface. As a first step toward such a goal, we consider the design of loops with a desired conformation. In this study, we focus on the H1 loop of the anti-hCG llama nanobody that exhibits a noncanonical conformation. We aim to "tilt" the stability of the H1 loop structure from a noncanonical conformation to a (humanized) type 1 canonical conformation by studying the effect of selected mutations to the amino acid sequence of the H1, H2, and proximal residues. We use all-atomistic, explicit-solvent, biased molecular dynamic simulations to simulate the wild-type and mutant loops in a prefolded framework. We thus find mutants with increasing propensity to form a stable type 1 canonical conformation of the H1 loop. Free energy landscapes reveal the existence of conformational isomers of the canonical conformation that may play a role in binding different antigenic surfaces. We also elucidate the approximate mechanism and kinetics of transitions between such conformational isomers by using a Markovian model. We find that a particular three-point mutant has the strongest thermodynamic propensity to form the H1 type 1 canonical structure but also to exhibit transitions between conformational isomers, while a different, more rigid three-point mutant has the strongest propensity to be kinetically trapped in such a canonical structure.
MeSH term(s)	Immunoglobulin Heavy Chains/chemistry ; Immunoglobulin Heavy Chains/genetics ; Kinetics ; Markov Chains ; Models, Molecular ; Point Mutation ; Protein Conformation ; Thermodynamics
Chemical Substances	Immunoglobulin Heavy Chains
Language	English
Publishing date	2013-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/jp3075496
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Article ; Online: Overcoming dissipation in the calculation of standard binding free energies by ligand extraction.

Velez-Vega, Camilo / Gilson, Michael K

Journal of computational chemistry

2013 Volume 34, Issue 27, Page(s) 2360–2371

Abstract: This article addresses calculations of the standard free energy of binding from molecular simulations in which a bound ligand is extracted from its binding site by steered molecular dynamics (MD) simulations or equilibrium umbrella sampling (US). Host- ... ...

Abstract	This article addresses calculations of the standard free energy of binding from molecular simulations in which a bound ligand is extracted from its binding site by steered molecular dynamics (MD) simulations or equilibrium umbrella sampling (US). Host-guest systems are used as test beds to examine the requirements for obtaining the reversible work of ligand extraction. We find that, for both steered MD and US, marked irreversibilities can occur when the guest molecule crosses an energy barrier and suddenly jumps to a new position, causing dissipation of energy stored in the stretched molecule(s). For flexible molecules, this occurs even when a stiff pulling spring is used, and it is difficult to suppress in calculations where the spring is attached to the molecules by single, fixed attachment points. We, therefore, introduce and test a method, fluctuation-guided pulling, which adaptively adjusts the spring's attachment points based on the guest's atomic fluctuations relative to the host. This adaptive approach is found to substantially improve the reversibility of both steered MD and US calculations for the present systems. The results are then used to estimate standard binding free energies within a comprehensive framework, termed attach-pull-release, which recognizes that the standard free energy of binding must include not only the pulling work itself, but also the work of attaching and then releasing the spring, where the release work includes an accounting of the standard concentration to which the ligand is discharged.
MeSH term(s)	Bridged Bicyclo Compounds/chemistry ; Bridged-Ring Compounds/chemistry ; Imidazoles/chemistry ; Ligands ; Molecular Dynamics Simulation ; Octanes/chemistry ; Spermine/chemistry ; Thermodynamics
Chemical Substances	Bridged Bicyclo Compounds ; Bridged-Ring Compounds ; Imidazoles ; Ligands ; Octanes ; cucurbit(7)uril ; Spermine (2FZ7Y3VOQX) ; cucurbit(6)uril (80262-44-8)
Language	English
Publishing date	2013-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1479181-X
ISSN	1096-987X ; 0192-8651
ISSN (online)	1096-987X
ISSN	0192-8651
DOI	10.1002/jcc.23398
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Article ; Online: Force and Stress along Simulated Dissociation Pathways of Cucurbituril-Guest Systems.

Velez-Vega, Camilo / Gilson, Michael K

Journal of chemical theory and computation

2012 Volume 8, Issue 3, Page(s) 966–976

Abstract: The field of host-guest chemistry provides computationally tractable yet informative model systems for biomolecular recognition. We applied molecular dynamics simulations to study the forces and mechanical stresses associated with forced dissociation of ... ...

Abstract	The field of host-guest chemistry provides computationally tractable yet informative model systems for biomolecular recognition. We applied molecular dynamics simulations to study the forces and mechanical stresses associated with forced dissociation of aqueous cucurbituril-guest complexes with high binding affinities. First, the unbinding transitions were modeled with constant velocity pulling (steered dynamics) and a soft spring constant, to model atomic force microscopy (AFM) experiments. The computed length-force profiles yield rupture forces in good agreement with available measurements. We also used steered dynamics with high spring constants to generate paths characterized by a tight control over the specified pulling distance; these paths were then equilibrated via umbrella sampling simulations and used to compute time-averaged mechanical stresses along the dissociation pathways. The stress calculations proved to be informative regarding the key interactions determining the length-force profiles and rupture forces. In particular, the unbinding transition of one complex is found to be a stepwise process, which is initially dominated by electrostatic interactions between the guest's ammoniums and the host's carbonyl groups, and subsequently limited by the extraction of the guest's bulky bicyclooctane moiety; the latter step requires some bond stretching at the cucurbituril's extraction portal. Conversely, the dissociation of a second complex with a more slender guest is mainly driven by successive electrostatic interactions between the different guest's ammoniums and the host's carbonyl groups. The calculations also provide information on the origins of thermodynamic irreversibilities in these forced dissociation processes.
Language	English
Publishing date	2012-01-20
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/ct2006902
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