SW1P 1WG The Interface Between Chemistry and Physics - 5500 Words

SW1P 1WG: An International Journal at the Interface Between Chemistry and Physics (Research Paper Sample) Content: This article was downloaded by: [88.233.181.231] On: 28 July 2015, At: 07:25Publisher: Taylor FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place, London, SW1P 1WGClick for updatesMolecular Physics: An International Journal at theInterface Between Chemistry and PhysicsPublication details, including instructions for authors and subscription information:/loi/tmph20Role of the n+1 amino acid residue on the deamidation of asparagine in pentapeptidesHasan H. Incea, F. Aylin Sungur Konuklarb, Ilke Ugurcde, ÃÆ'. Alaz Ozcand, Maryam Sayadif, Michael Feigg Viktorya Aviyenteda Department of Chemistry, Michigan State University, East Lansing, USAb Informatics Institute, Computational Science and Engineering Division, Istanbul TechnicalUniversity, Istanbul, Turkeyc UniversitÃÆ' de Lorraine, Vandoeuvre-les-Nancy, Franced Department of Chemistry, BogaziÃÆ'i University, Istanbul, Turkeye CNRS, Vandoeuvre-les-Nancy, Fra ncef Kim Lab, University of Toronto, Toronto, Canadag Department of Chemistry and Department of Biochemistry Molecular Biology, MichiganState University, East Lansing, USA Published online: 27 Jul 2015.To cite this article: Hasan H. Ince, F. Aylin Sungur Konuklar, Ilke Ugur, ÃÆ'. Alaz Ozcan, Maryam Sayadi, Michael Feig ViktoryaAviyente (2015): Role of the n+1 amino acid residue on the deamidation of asparagine in pentapeptides, Molecular Physics: An International Journal at the Interface Between Chemistry and Physics, DOI: 10.1080/00268976.2015.1068394To link to this article: http://dx.doi.org/10.1080/00268976.2015.1068394PLEASE SCROLL DOWN FOR ARTICLETaylor Francis makes every effort to ensure the accuracy of all the information (the "Contentà ¢Ã¢â€š ¬Ã‚ ) contained in the publications on our platform. However, Taylor Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of th e Content. Any opinions and views expressed in this publication are the opinions and views of the authors, andare not the views of or endorsed by Taylor Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use ofthe Content.This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in anyform to anyone is expressly forbidden. Terms Conditions of access and use can be found at http:///page/terms-and-conditionsMolecular Physics, 2015 http://dx.doi.org/10.1080/00268976.2015.1068394RESEARCH ARTICLERole o f the n + 1 amino acid residue on the deamidation of asparagine in pentapeptidesHasan H. Incea , F. Aylin Sungur Konuklarb , Ilke Ugurc , d , e , O ¨ . Alaz Ozcand , Maryam Sayadif , Michael Feigg andViktorya Aviyented , à ¢a Department of Chemistry, Michigan State University, East Lansing, USA; b Informatics Institute, Computational Science andEngineering Division, Istanbul Technical University, Istanbul, Turkey; c Universite ´ de Lorraine, Vandoeuvre-les-Nancy, France;d Department of Chemistry, Bogazic ¸i University, Istanbul, Turkey; e CNRS, Vandoeuvre-les-Nancy, France; f Kim Lab, University of Toronto, Toronto, Canada; g Department of Chemistry and Department of Biochemistry Molecular Biology, Michigan State University, East Lansing, USA(Received 29 March 2015; accepted 26 June 2015)Deamidation plays an important role in biochemical phenomena such as aging. The role of the n + 1 residue on the deamidation of asparagine (asparagine being the nth residue) in three pentapeptide chains (GGNGG, GGNMG and GGNIG) has been analysed with hybrid computational tools. Potentials of mean force at 300 K were calculated from the MD/replica exchange simulations using weighted histogram analysis (WHAM) in explicit water. The snapshots were clustered taking into account the requirements of the plausible deamidation mechanisms, as such the tautomerisation of the asparagine side chain as initial step has been confirmed, based on the proximity of water to the deamidation site. The ultimate goal being to gain an insight on the peptide backbone N-H acidity, quantum mechanical calculations have been carried out. For this purpose, the distribution of / , 2 / and end-to-end distances deduced from the WHAM diagrams have been considered and a total of 110 structures have been sampled. These neutral pentapeptides as well as their corresponding anions have beenoptimised (B3LYP/6-31 ++ G(d,p)) in implicit water in order to gain an insight on the pepti de backbone N-H acidity. In thisstudy, we have shown that the open conformations of the neutrals and the anions, which display a ÃŽÂ ² sheet like structure arewell populated and their pKa s rank in the same order as the deamidating half-lives, that is the peptides that deaminate fastest can more readily access conformations that are more acidic.Keywords: deamidation; peptide; modelling1. IntroductionDeamidation is the conversion of the amide group on the side chain of an amino acid residue to a carboxylate or car- boxylic acid depending on the pH of the medium. Under physiological conditions, proteins spontaneously degrade via physical and chemical processes. It was proposed that accumulation of protein defects, resulting from deamida- tion, may be one of the main causes of human aging [1]. Two of the twenty ordinary amino acid residues in peptides and proteins, asparagine (Asn) and glutamine (Gln), are un- stable under physiological conditions [2]. Deamidation of Asn or Gln in troduces a negative charge at the deamidation residue, and thus the structure of the deamidating peptide or protein changes. The conversion of the neutral amide side chain to the negatively charged carboxylate causes time dependent changes in conformation and limits the life- time of peptides and proteins [3à ¢Ã¢â€š ¬6]. It has been suggested that sequence-dependent non-enzymatic amide hydrolysis, deamidation of glutaminyl and asparaginyl residues in pep- tides and proteins may serve as a general molecular timer of biological processes [7].The non-enzymatic deamidation is also detected in pep- tides in vitro. The chemical instability introduced by this re- action in vitro causes several problems in pharmaceuticals. For instance, growth hormone-releasing factors were found to lose their biological activities because of being subject to deamidation during storage [8]. This major instability as- cribed to deamidation was observed years before the recent developments in engineered prot ein drugs. Currently, con- trolling the rate of deamidation is one of the major aspects of protein therapeutics optimisation, since it is one of the most commonly occurred degradations in peptides [9,10].Under neutral and basic conditions, the deamidation is base catalysed and the products are a mixture of as- partate (Asp), and iso-aspartate (Iso-Asp). Production of Iso-Asp requires cleavage of the peptide backbone. The experimentally isolated cyclic imide intermediate (succin- imide) justifies the backbone contribution in basic and neu- tral media [11]. The deprotonation of the peptide bond nitrogen is necessary for succinimide-mediated deami- dation and isomerisation. Capasso et al. defined succin- imide formation as the rate determining step of the overallDownloaded by [88.233.181.231] at 07:25 28 July 2015à ¢ Corresponding author. Email: aviye@boun.edu.trC 2015 Taylor FrancisScheme 1. Reactants and products of Asn deamidation.reaction [12]. The cyclic imide then hydro lyses at either one of the two carbonyls to yield a mixture of Asp and Iso-Asp residues. The ratio of L-Asp to L-iso-Asp was experimen- tally found to be 3:1 (Scheme 1).Tyler-Cross and Schirch [13] and Robinson et al. [1] found that the residue immediately following the Asn (on the C-terminal side) has a large effect on the deamidation rate. The fastest deamidation rates, on the time scale of a day at neutral pH, were observed for sequences containing - Asn-Gly- [1]. Kosky et al. [14], Xie et al. [15] and Robinson et al. [16à ¢Ã¢â€š ¬18] found that secondary and tertiary structures generally reduce deamidation rates as compared to peptides with the same sequence. Peters and Trout claim that the conversion of Asn to succinimide is the rate limiting step in the deamidation [19].The most rapid deamidation was observed when then + 1 residue is glycine (Gly). The facilitating effect of Glyon deamidation with respect to other residues was explainedby several factors:(1) Steric hindrance : The size of groups on the ÃŽ- carbon of n + 1 residue is seen to control the rateof deamidation. However, the degradation rates are not linearly correlated with the size of the residues [20,21].(2) Backbone amide acidity: Experimental studies have related the deamidation rate to the hydrogen ex- change rate constants of the backbone amide hy-drogen of the n + 1 residue and have created a newperspective to the facilitating effect of Gly [22]. Theassumption here was that the rate of deamidation is directly correlated to acidity of backbone amide hy-drogen of n + 1. This assumption fairly explained the impact of n + 1 residue for several non- Glyresidues. However, the relative rate of the peptideswit...