Can the protonation state of histidine residues be determined from molecular dynamics simulations?

Uranga, Jon; Mikulskis, Paulius; Genheden, Samuel; Ryde, Ulf

doi:10.1016/j.comptc.2012.09.025

Cited by 32 publications

(40 citation statements)

References 27 publications

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“…All Asp and Glu residues were negatively charged, and all Lys and Arg residues were positively charged. The histidine at the binding site (H158) was protonated on the ND1 atom, and the other three histidine residues were protonated on the NE2 atom, in accordance with previous studies and NMR measurements . The protein was described with the Amber99SB force field, whereas the ligands were described with the general Amber force field with charges obtained by the restrained electrostatic potential method .…”

Section: Methodssupporting

confidence: 76%

Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model

2015

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The most general way to improve the accuracy of binding-affinity calculations for protein-ligand systems is to use quantum-mechanical (QM) methods together with rigorous alchemical-perturbation (AP) methods. We explore this approach by calculating the relative binding free energy of two synthetic disaccharides binding to galectin-3 at a reasonably high QM level (dispersion-corrected density functional theory with a triple-zeta basis set) and with a sufficiently large QM system to include all short-range interactions with the ligand (744-748 atoms). The rest of the protein is treated as a collection of atomic multipoles (up to quadrupoles) and polarizabilities. Several methods for evaluating the binding free energy from the 3600 QM calculations are investigated in terms of stability and accuracy. In particular, methods using QM calculations only at the endpoints of the transformation are compared with the recently proposed non-Boltzmann Bennett acceptance ratio (NBB) method that uses QM calculations at several stages of the transformation. Unfortunately, none of the rigorous approaches give sufficient statistical precision. However, a novel approximate method, involving the direct use of QM energies in the Bennett acceptance ratio method, gives similar results as NBB but with better precision, ∼3 kJ/mol. The statistical error can be further reduced by performing a greater number of QM calculations.

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Section: Methodssupporting

confidence: 76%

Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model

2015

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“…The protonation state of histidine residues were assigned by analyzing the local hydrogen-bonding network. 69 Additionally, unresolved atoms were filled in manually to construct a full side chain for GLU19 of 1DYZ. The protein structures were solvated in water inside a 98.6726Å truncated octahedron.…”

Section: Methodsmentioning

confidence: 99%

An Angular Overlap Model for Cu(II) Ion in the AMOEBA Polarizable Force Field

Xiang

Ponder

2013

J. Chem. Theory Comput.

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An extensible polarizable force field for transition metal ion was developed based on AMOEBA and the angular overlap model (AOM) with consistent treatment of electrostatics for all atoms. Parameters were obtained by fitting molecular mechanics (MM) energies to various ab initio gas-phase calculations. The results of parameterization were presented for copper (II) ion ligated to water and model fragments of amino acid residues involved in the copper binding sites of type 1 copper proteins. Molecular dynamics (MD) simulations were performed on aqueous copper (II) ion at various temperatures, as well as plastocyanin (1AG6) and azurin (1DYZ). Results demonstrated that the AMOEBA-AOM significantly improves the accuracy of classical MM in a number of test cases when compared to ab initio calculations. The Jahn-Teller distortion for hexa-aqua copper (II) complex was handled automatically without specifically designating axial and in-plane ligands. Analyses of MD trajectories resulted in a 6-coordination first solvation shell for aqueous copper (II) ion and a 1.8ns average residence time of water molecules. The ensemble average geometries of 1AG6 and 1DYZ copper binding sites were in general agreement with X-ray and previous computational studies.

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“…They cannot be derived from the crystal structure. To determine the protonation state of His116, we thought to use the observation that the actual protonation state shows the lowest RMSD value of the histidine side chain and the surrounding residues in a MD simulation [37]. We thus performed two independent MD simulations of empty B*27:09 and B*27:09/IF9 for each possible protonation state.…”

Section: Protonation State Of Residue 116 Resolved From MD Simulationsmentioning

confidence: 99%

F pocket flexibility influences the tapasin dependence of two differentially disease‐associated MHC Class I proteins

et al. 2015

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The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.Keywords: Ankylosing spondylitis r HLA-B27 r Major histocompatibility complex r Molecular dynamics r Natively unstructured proteins r Protein folding r Simulations Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction MHC class I molecules are heterotrimeric proteins that transport antigenic peptides to the cell surface and present them to cytotoxic T cells. They consist of the transmembrane heavy chain (HC), the noncovalently associated light chain beta-2 microglobulin (β 2 m), and an antigenic peptide of eight to ten amino acids. The Correspondence: Prof. Sebastian Springer e-mail: s.springer@jacobs-university.de extracellular part of the heavy chain comprises the α 1 , α 2 , and α 3 domains. The α 1 and α 2 domains form the peptide-binding groove, a superdomain that consists of an antiparallel beta sheet surmounted by two alpha helices, between which the peptide binds [1,2].In the cell, peptide binding to class I is a multistep process within the ER. It involves the peptide-loading complex, which consists of the peptide transporter associated with antigen processing (TAP) that transports peptides from the cytosol into the ER lumen [3] and several chaperone proteins such as tapasin, which binds both to the class I molecule and TAP [4,5].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1248-1257 Molecular immunology 1249The sequence of peptides that can bind to class I is determined by interactions with the amino acid side chains of the peptide-binding groove. The high sequence polymorphism of the peptide-binding groove in human class I molecules (human leukocyte antigens, HLA-A, -B, and -C) means that different allotypes bind different peptides; thus, individual HLA allotypes-such as HLA-B27-support-specific immune responses and are statistically associated with disease [6,7]. Among the subtypes of HLA-B27 [8,9], HLA-B*27:05 (B*27:05) shows a very strong statistical association with spondyloarthropathies such as ankylosing spondylitis (AS), in contr...

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Can the protonation state of histidine residues be determined from molecular dynamics simulations?

Cited by 32 publications

References 27 publications

Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model

Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model

An Angular Overlap Model for Cu(II) Ion in the AMOEBA Polarizable Force Field

F pocket flexibility influences the tapasin dependence of two differentially disease‐associated MHC Class I proteins

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