MRP.py: A Parametrizer of Post-Translationally Modified Residues

Sahrmann, Patrick G.; Donnan, Patrick H.; Merz, Kenneth M.; Mansoorabadi, Steven O.; Goodwin, Douglas C.

doi:10.1021/acs.jcim.0c00472

Cited by 4 publications

(4 citation statements)

References 37 publications

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“…As such, the MM force field largely dictates the quality of these atomistic simulations. A number of force fields for nonstandard amino acids were derived previously, and tools for the development of such force fields were reported. , AMBER parameters for 32 frequently occurring post-translational modifications were derived which were later extended to include 147 noncanonical amino acids. Petrov et al developed force field parameters for 256 different types of PTMs compatible with the GROMOS force field and later provided a web tool to incorporate PTMs into a 3D protein structure .…”

Section: Introductionmentioning

confidence: 99%

“…A number of force fields for nonstandard amino acids were derived previously, and tools for the development of such force fields were reported. 14,15 AMBER parameters for 32 frequently occurring post-translational modifications were derived 16 which were later extended to include 147 noncanonical amino acids. Petrov incorporate PTMs into a 3D protein structure.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Additive CHARMM36 Force Field for Nonstandard Amino Acids

Croitoru

Park

Kumar

et al. 2021

J. Chem. Theory Comput.

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Nonstandard amino acids are both abundant in nature, where they play a key role in various cellular processes, and can be synthesized in laboratories, for example, for the manufacture of a range of pharmaceutical agents. In this work, we have extended the additive all-atom CHARMM36 and CHARMM General force field (CGenFF) to a large set of 333 nonstandard amino acids. These include both amino acids with nonstandard side chains, such as post-translationally modified and artificial amino acids, as well as amino acids with modified backbone groups, such as chromophores composed of several amino acids. Model compounds representative of the nonstandard amino acids were parametrized for protonation states that are likely at the physiological pH of 7 and, for some more common residues, in both D-and L-stereoisomers. Considering all protonation, tautomeric, and stereoisomeric forms, a total of 406 nonstandard amino acids were parametrized. Emphasis was placed on the quality of both intra-and intermolecular parameters. Partial charges were derived using quantum mechanical (QM) data on model compound dipole moments, electrostatic potentials, and interactions with water. Optimization of all intramolecular parameters, including torsion angle parameters, was performed against information from QM adiabatic potential energy surface (PES) scans. Special emphasis was put on the quality of terms corresponding to PES around rotatable dihedral angles. Validation of the force field was based on molecular dynamics simulations of 20 protein complexes containing different nonstandard amino acids. Overall, the presented parameters will allow for computational studies of a wide range of proteins containing nonstandard amino acids, including natural and artificial residues.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Additive CHARMM36 Force Field for Nonstandard Amino Acids

Croitoru

Park

Kumar

et al. 2021

J. Chem. Theory Comput.

View full text Add to dashboard Cite

show abstract

“…The protein and ions were parameterized with the AMBER14SB ( 81 ) forcefield, and the waters were parameterized with the TIP3P parameter set. The parameters for the Cys 101 -thioimidate intermediate (CYT) residue were determined using MRP.py ( 82 ), a software package for parametrization of posttranslationally modified residues, which uses AmberTools ( 83 ) and Gaussian 16 ( 84 ) to determine the bonded and nonbonded parameters and partial charges.…”

Section: Methodsmentioning

confidence: 99%

Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography

Smith,

Dasgupta,

Wych

et al. 2024

Sci. Adv.

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Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser to observe catalysis in a designed mutant isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations, and formation of the thioimidate intermediate selects for catalytically competent substates. The influence of cysteine ionization on the ICH ensemble is validated by determining structures of the enzyme at multiple pH values. Large molecular dynamics simulations in crystallo and time-resolved electron density maps show that Asp 17 ionizes during catalysis and causes conformational changes that propagate across the dimer, permitting water to enter the active site for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

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“…The protein and ions were parameterized with the AMBER14SB 78 forcefield and the waters were parameterized with the TIP3P parameter set. The parameters for the Cys101 thioimidate intermediate (CYT) residue were determined using MRP.py 79 , a software package for parametrization of post-translationally modified residues, which uses AmberTools 80 and Gaussian 16 81 to determine the bonded and non-bonded parameters and partial charges. Supercell systems were subjected to iterative rounds of solvation and equilibration using gmx solvate and gmx mdrun to bring the systems up to pressure in the constant particle number, volume, and temperature (NVT) ensemble (at 300K).…”

Section: Crystalline Molecular Dynamics Simulationmentioning

confidence: 99%

Changes in an Enzyme Ensemble During Catalysis Observed by High Resolution XFEL Crystallography

Smith,

Dasgupta,

Wych

et al. 2023

Preprint

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Enzymes populate ensembles of structures with intrinsically different catalytic proficiencies that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL) to observe catalysis in a designed mutant (G150T) isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations and formation of the thioimidate catalytic intermediate selects for catalytically competent substates. A prior proposal for active site cysteine charge-coupled conformational changes in ICH is validated by determining structures of the enzyme over a range of pH values. A combination of large molecular dynamics simulations of the enzyme in crystallo and time-resolved electron density maps shows that ionization of the general acid Asp17 during catalysis causes additional conformational changes that propagate across the dimer interface, connecting the two active sites. These ionization-linked changes in the ICH conformational ensemble permit water to enter the active site in a location that is poised for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.

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MRP.py: A Parametrizer of Post-Translationally Modified Residues

Cited by 4 publications

References 37 publications

Additive CHARMM36 Force Field for Nonstandard Amino Acids

Additive CHARMM36 Force Field for Nonstandard Amino Acids

Changes in an enzyme ensemble during catalysis observed by high-resolution XFEL crystallography

Changes in an Enzyme Ensemble During Catalysis Observed by High Resolution XFEL Crystallography

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