Parameterization of Unnatural Amino Acids with Azido and Alkynyl R-Groups for Use in Molecular Simulations

Smith, Addison K; Wilkerson, Joshua W.; Knotts, Thomas A.

doi:10.1021/acs.jpca.0c04605

Cited by 8 publications

(7 citation statements)

References 45 publications

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“…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 . For the additive CHARMM force field, a number of nonstandard amino acids were parametrized specifically in previous works. − Seventeen artificial amino acids were parametrized in our previous work . CHARMM compatible topologies were created for 210 nonstandard alpha amino acid side chains and were made available as an online service .…”

Section: Introductionmentioning

confidence: 99%

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%

Additive CHARMM36 Force Field for Nonstandard Amino Acids

Croitoru

Park

Kumar

et al. 2021

J. Chem. Theory Comput.

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“…The CHARMM-compatible topology for the modified ahyC nucleotide tail was built on a B-DNA structure based on azido and alkynyl group parameters optimized by Smith et al. ( 28 ). Molecular dynamics simulations were performed with GROMACS program (v. 2020.4) ( 29 , 30 ) using CHARMM36 force field ( 31 ) in water containing 0.15 M NaCl.…”

Section: Methodsmentioning

confidence: 99%

Enhanced nucleosome assembly at CpG sites containing an extended 5-methylcytosine analogue

Tomkuvienė

Meier

Ikasalaitė

et al. 2022

Nucleic Acids Research

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Methylation of cytosine to 5-methylcytosine (mC) at CpG sites is a prevalent reversible epigenetic mark in vertebrates established by DNA methyltransferases (MTases); the attached methyl groups can alter local structure of DNA and chromatin as well as binding of dedicated proteins. Nucleosome assembly on methylated DNA has been studied extensively, however little is known how the chromatin structure is affected by larger chemical variations in the major groove of DNA. Here, we studied the nucleosome formation in vitro on DNA containing an extended 5mC analog, 5-(6-azidohex-2-ynyl)cytosine (ahyC) installed at biological relevant CpG sites. We found that multiple ahyC residues on 80-Widom and Hsp70 promoter DNA fragments proved compatible with nucleosome assembly. Moreover, unlike mC, ahyC increases the affinity of histones to the DNA, partially altering nucleosome positioning, stability, and the action of chromatin remodelers. Based on molecular dynamics calculations, we suggest that these new features are due to increased DNA flexibility at ahyC-modified sites. Our findings provide new insights into the biophysical behavior of modified DNA and open new ways for directed design of synthetic nucleosomes.

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“…The proteins were modeled using the CHARMM36 force field with CMAP correction. , pAz was simulated using recently developed parameters by Smith et al SHAKE was used for bonds to hydrogen atoms. The NTER and CTER patches were used, and histidine was modeled as charge-neutral HSD.…”

Section: Methodsmentioning

confidence: 99%

The Effects of p-Azidophenylalanine Incorporation on Protein Structure and Stability

Wilkerson

Smith

Wilding

et al. 2020

J. Chem. Inf. Model.

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Functionalization is often needed to harness the power of proteins for beneficial use but can cause losses to stability and/or activity. State of the art methods to limit these deleterious effects accomplish this by substituting an amino acid in the wildtype molecule into an unnatural amino acid, such as pazidophenylalanine (pAz), but selecting the residue for substitution a priori remains an elusive goal of protein engineering. The results of this work indicate that all-atom molecular dynamics simulation can be used to determine whether substituting pAz for a natural amino acid will be detrimental to experimentally determined protein stability. These results offer significant hope that local deviations from wild-type structure caused by pAz incorporation observed in simulations can be a predictive metric used to reduce the number of costly experiments that must be done to find active proteins upon substitution with pAz and subsequent functionalization.

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Parameterization of Unnatural Amino Acids with Azido and Alkynyl R-Groups for Use in Molecular Simulations

Cited by 8 publications

References 45 publications

Additive CHARMM36 Force Field for Nonstandard Amino Acids

Additive CHARMM36 Force Field for Nonstandard Amino Acids

Enhanced nucleosome assembly at CpG sites containing an extended 5-methylcytosine analogue

The Effects of p-Azidophenylalanine Incorporation on Protein Structure and Stability

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