Evaluating amber force fields using computed NMR chemical shifts

Koes, David Ryan; Vries, John K.

doi:10.1002/prot.25350

Cited by 11 publications

(8 citation statements)

References 45 publications

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“…Moreover, the FF nanotube is similar to a globular protein in that FF orders with hydrophobic and hydrophilic layers. The IpolQ force fields more closely reproduce the NMR chemical shifts relative to other Amber force fields of large globular proteins further supporting our choice in the force field …”

Section: Methodssupporting

confidence: 58%

Initial Aggregation and Ordering Mechanism of Diphenylalanine from Microsecond All-Atom Molecular Dynamics Simulations

2018

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Self-assembled diphenylalanine (FF) nanostructures have recently been demonstrated to be interesting materials for antibacterial and anticancer applications. These applications, among others, seek to take advantage of the high-order and resulting appealing physical properties of FF nanostructures by modifying the peptide in some way to achieve specific functionality. To rationally design modifications to the dipeptide that allow for this behavior, the driving forces of FF self-assembly must be understood. Molecular simulations have been utilized to assess these properties but have yielded conflicting conclusions due to inconsistencies in models chosen as well as the lack of quantitative analyses on the specific driving forces. Here, we present an all-atom explicit solvent molecular dynamics-based study on different length scales of FF aggregation. We utilize a free energy decomposition analysis as well as a dimer cluster analysis to identify the initial aggregation driving force to be FF intermolecular electrostatics, whereas solvent-mediated forces drive crystal growth. These data are consistent with the hypothesis that all hydrophobic dipeptides will have a similar initial aggregation mechanism until a critical aggregate size is reached, at which point crystallization occurs and subsequent crystal growth is dominated by solvent-mediated forces. We demonstrate that this proposed mechanism is testable by infrared spectroscopy focusing on the blueshift of the amide I peak as well as the ordering of the carboxylate peak.

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Section: Methodssupporting

confidence: 58%

Initial Aggregation and Ordering Mechanism of Diphenylalanine from Microsecond All-Atom Molecular Dynamics Simulations

2018

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“…In the absence of high-quality structural data, we used NMR chemical shifts to validate the obtained SH3:Sos1-X′ model. This approach has been introduced following the development of structure-based methods for calculation of protein chemical shifts 57–61 . Like others, we use secondary chemical shifts, , that are supposedly free from the effect of primary structure and sensitive only to higher-order (secondary, tertiary, etc.)…”

Section: Resultsmentioning

confidence: 99%

Molecular Dynamics model of peptide-protein conjugation: case study of covalent complex between Sos1 peptide and N-terminal SH3 domain from Grb2

Luzik

Rogacheva

Izmailov

et al. 2019

Sci Rep

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We have investigated covalent conjugation of VPPPVPPRRRX′ peptide (where X′ denotes Nε-chloroacetyl lysine) to N-terminal SH3 domain from adapter protein Grb2. Our experimental results confirmed that the peptide first binds to the SH3 domain noncovalently before establishing a covalent linkage through reaction of X′ with the target cysteine residue C32. We have also confirmed that this reaction involves a thiolate-anion form of C32 and follows the SN2 mechanism. For this system, we have developed a new MD-based protocol to model the formation of covalent conjugate. The simulation starts with the known coordinates of the noncovalent complex. When two reactive groups come into contact during the course of the simulation, the reaction is initiated. The reaction is modeled via gradual interpolation between the two sets of force field parameters that are representative of the noncovalent and covalent complexes. The simulation proceeds smoothly, with no appreciable perturbations to temperature, pressure or volume, and results in a high-quality MD model of the covalent complex. The validity of this model is confirmed using the experimental chemical shift data. The new MD-based approach offers a valuable tool to explore the mechanics of protein-peptide conjugation and build accurate models of covalent complexes.

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“…The ff15ipq force field reportedly describes the strength of protein salt bridges reasonably well compared to other force fields 40,49 and reproduces chemical shifts more accurately. 50 CHARMM36m (the latest variant of the CHARMM pair-additive protein force field) was also developed for modeling both structured proteins and IDPs although it still provides relatively compact IDPs. 44 It utilizes NBFIX potential to specifically decrease the salt-bridge strength of arginine−aspartate/glutamate interactions.…”

Section: ■ Methodsmentioning

confidence: 99%

Role of Fine Structural Dynamics in Recognition of Histone H3 by HP1γ(CSD) Dimer and Ability of Force Fields to Describe Their Interaction Network

Pokorná

Krepl

Bártová

et al. 2019

J. Chem. Theory Comput.

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Human heterochromatin protein 1 (HP1) is a key factor in heterochromatin formation and maintenance. Its chromo-shadow domain (CSD) homodimerizes, and the HP1 dimer acts as a hub, transiently interacting with diverse binding partner (BP) proteins. We analyze atomistic details of interactions of the HP1γ(CSD) dimer with one of its targets, the histone H3 N-terminal tail, using molecular dynamics (MD) simulations. The goal is to complement the available X-ray crystallography data and unravel potential dynamic effects in the molecular recognition. Our results suggest that HP1(CSD)–BP recognition involves structural dynamics of both partners, including structural communication between adjacent binding pockets that may fine-tune the sequence recognition. For example, HP1 Trp174 sidechain substates may help in distinguishing residues bound in the conserved HP1(CSD) ±2 hydrophobic pockets. Further, there is intricate competition between the binding of negatively charged HP1 C-terminal extension and solvent anions near the ±2 hydrophobic pockets, which is also influenced by the BP sequence. Phosphorylated H3 Y41 can interact with the same site. We also analyze the ability of several pair-additive force fields to describe the protein–protein interface. ff14SB and ff99SB-ILDN* provide the closest correspondence with the crystallographic model. The ff15ipq local dynamics are somewhat less consistent with details of the experimental structure, while larger perturbations of the interface commonly occur in CHARMM36m simulations. The balance of some interactions, mainly around the anion binding site, also depends on the ion parameters. Some differences between the simulated and experimental structures are attributable to crystal packing.

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Evaluating amber force fields using computed NMR chemical shifts

Cited by 11 publications

References 45 publications

Initial Aggregation and Ordering Mechanism of Diphenylalanine from Microsecond All-Atom Molecular Dynamics Simulations

Initial Aggregation and Ordering Mechanism of Diphenylalanine from Microsecond All-Atom Molecular Dynamics Simulations

Molecular Dynamics model of peptide-protein conjugation: case study of covalent complex between Sos1 peptide and N-terminal SH3 domain from Grb2

Role of Fine Structural Dynamics in Recognition of Histone H3 by HP1γ(CSD) Dimer and Ability of Force Fields to Describe Their Interaction Network

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