Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin

Cool, Austin M; Lindert, Steffen

doi:10.1021/acs.jcim.2c00508

Cited by 10 publications

(18 citation statements)

References 49 publications

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“…Umbrella sampling (US) has shown efficiency for studying binding free energy and kinetic details in exploring drug binding/dissociating pathways. − Here, in order to fully capture the thermodynamic and kinetic characteristics of a PROTAC interacting with the POI and E3 ligase, US was performed on the seven PROTAC systems based on the disintegration trajectories of the RAMD simulations.…”

Section: Methodsmentioning

confidence: 99%

Uncovering the Kinetic Characteristics and Degradation Preference of PROTAC Systems with Advanced Theoretical Analyses

Tang

Wang

Xiang

et al. 2023

JACS Au

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Proteolysis-targeting chimeras (PROTACs), which can selectively induce the degradation of target proteins, represent an attractive technology in drug discovery. A large number of PROTACs have been reported, but due to the complicated structural and kinetic characteristics of the target-PROTAC-E3 ligase ternary interaction process, the rational design of PROTACs is still quite challenging. Here, we characterized and analyzed the kinetic mechanism of MZ1, a PROTAC that targets the bromodomain (BD) of the bromodomain and extra terminal (BET) protein (Brd2, Brd3, or Brd4) and von Hippel-Lindau E3 ligase (VHL), from the kinetic and thermodynamic perspectives of view by using enhanced sampling simulations and free energy calculations. The simulations yielded satisfactory predictions on the relative residence time and standard binding free energy (r p > 0.9) for MZ1 in different Brd BD -MZ1-VHL ternary complexes. Interestingly, the simulation of the PROTAC ternary complex disintegration illustrates that MZ1 tends to remain on the surface of VHL with the BD proteins dissociating alone without a specific dissociation direction, indicating that the PROTAC prefers more to bind with E3 ligase at the first step in the formation of the target-PROTAC-E3 ligase ternary complex. Further exploration of the degradation difference of MZ1 in different Brd systems shows that the PROTAC with higher degradation efficiency tends to leave more lysine exposed on the target protein, which is guaranteed by the stability (binding affinity) and durability (residence time) of the target-PROTAC-E3 ligase ternary complex. It is quite possible that the underlying binding characteristics of the Brd BD -MZ1-VHL systems revealed by this study may be shared by different PROTAC systems as a general rule, which may accelerate rational PROTAC design with higher degradation efficiency.

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Section: Methodsmentioning

confidence: 99%

Uncovering the Kinetic Characteristics and Degradation Preference of PROTAC Systems with Advanced Theoretical Analyses

Tang

Wang

Xiang

et al. 2023

JACS Au

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“…The hydrophobic patch serves as an attractive target for increasing Ca 2+ sensitivity via small molecules. Additionally, the hydrophobic patch and entire troponin complex have been the focus of numerous in silico studies to capture the proteins dynamics of hydrophobic patch opening 30, 31, 32, 33, 34, 35, 36, 37 , and cTnI sp binding 38, 39, 40, 41, 42 .…”

Section: Introductionmentioning

confidence: 99%

Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship

Hantz

Tikunova

Belevych

et al. 2023

Preprint

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Despite large investments from academia and industry, heart failure, which results from a disruption of the contractile apparatus, remains a leading cause of death. Cardiac muscle contraction is a calcium-dependent mechanism, which is regulated by the troponin protein complex (cTn) and specifically by the N-terminal domain of its calcium binding subunit (cNTnC). There is an increasing need for the development of small molecules that increase calcium sensitivity without altering systolic calcium concentration, thereby strengthening cardiac function. Here, we examined the effect of our previously identified calcium sensitizing small molecule, ChemBridge compound 7930079, in the context of several homologous muscle systems. The effect of this molecule on force generation in isolated cardiac trabeculae and slow skeletal muscle fibers was measured. Furthermore, we explored the use of Gaussian accelerated molecular dynamics in sampling highly predictive receptor conformations based on NMR derived starting structures. Additionally, we took a rational computational approach for lead optimization based on lipophilic diphenyl moieties. This led to the identification of three novel low affinity binders, which had similar binding affinities to known positive inotrope trifluoperazine. The most potent identified calcium sensitizer was compound 16 with an apparent affinity of 117±17 μM.

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“…Dvornikov et al explored the effect of the R145W mutation on myofilament length-dependent activation (LDA) and found that the mutation does not affect LDA but does increase the sensitivity of the myofilament to Ca 2+ . Moreover, biochemical assays and functional experiments on the R145G mutation converged on the finding that this mutation causes an increase in myofilament Ca 2+ -sensitivity , and reduces the ability of cTnI to inhibit activation of cardiac muscle. , Computational efforts have also explored the effect that these cTnI mutations can have on the thermodynamics of the cTnC HP opening event. ,− Our lab and others have successfully shown the potential of computational tools as a viable option for studying cTn dynamics for the purpose of computationally aided drug discovery − and Ca 2+ -binding simulations. − …”

Section: Introductionmentioning

confidence: 99%

Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations

Cool

Lindert

2023

J. Chem. Inf. Model.

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The cardiac thin filament comprises F-actin, tropomyosin, and troponin (cTn). cTn is composed of three subunits: troponin C (cTnC), troponin I (cTnI), and troponin T (cTnT). To computationally study the effect of the thin filament on cTn activation events, we employed targeted molecular dynamics followed by umbrella sampling using a model of the thin filament to measure the thermodynamics of cTn transition events. Our simulations revealed that the thin filament causes an increase in the free energy required to open the cTnC hydrophobic patch and causes a more favorable interaction between this region and the cTnI switch peptide. Mutations to the cTn complex can lead to cardiomyopathy, a collection of diseases that present clinically with symptoms of hypertrophy or dilation of the cardiac muscle, leading to impairment of the heart's ability to function normally and ultimately myocardial infarction or heart failure. Upon introduction of cardiomyopathic mutations to R145 of cTnI, we observed a general decrease in the free energy of opening the cTnC hydrophobic patch, which is on par with previous experimental results. These mutations also exhibited a decrease in electrostatic interactions between cTnI-R145 and actin-E334. After introduction of a small molecule to the wild-type cTnI−actin interface to intentionally disrupt intersubunit contacts, we successfully observed similar thermodynamic consequences and disruptions to the same protein−protein contacts as observed with the cardiomyopathic mutations. Computational studies utilizing the cTn complex in isolation would have been unable to observe these effects, highlighting the importance of using a more physiologically relevant thin-filament model to investigate the global consequences of cardiomyopathic mutations to the cTn complex.

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Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin

Cited by 10 publications

References 49 publications

Uncovering the Kinetic Characteristics and Degradation Preference of PROTAC Systems with Advanced Theoretical Analyses

Uncovering the Kinetic Characteristics and Degradation Preference of PROTAC Systems with Advanced Theoretical Analyses

Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship

Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations

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