{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:06:48Z","timestamp":1787069208709,"version":"build-2736575974"},"reference-count":72,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T00:00:00Z","timestamp":1535673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Spontaneous deamidation in the Asn-Gly-Arg (NGR) motif that yields an isoAsp-Gly-Arg (isoDGR) sequence has recently attracted considerable attention because of the possibility of application to dual tumor targeting. It is well known that Asn deamidation reactions in peptide chains occur via the five-membered ring succinimide intermediate. Recently, we computationally showed by the B3LYP density functional theory method, that inorganic phosphate and the Arg side chain can catalyze the NGR deamidation using a cyclic peptide, c[CH2CO\u2013NGRC]\u2013NH2. In this previous study, the tetrahedral intermediate of the succinimide formation was assumed to be readily protonated at the nitrogen originating from the Asn side chain by the solvent water before the release of an NH3 molecule. In the present study, we found a new mechanism for the decomposition of the tetrahedral intermediate that does not require the protonation by an external proton source. The computational method is the same as in the previous study. In the new mechanism, the release of an NH3 molecule occurs after a proton exchange between the peptide and the phosphate and conformational changes. The rate-determining step of the overall reaction course is the previously reported first step, i.e., the cyclization to form the tetrahedral intermediate.<\/jats:p>","DOI":"10.3390\/molecules23092217","type":"journal-article","created":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T10:57:52Z","timestamp":1535713072000},"page":"2217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Phosphate-Catalyzed Succinimide Formation from an NGR-Containing Cyclic Peptide: A Novel Mechanism for Deammoniation of the Tetrahedral Intermediate"],"prefix":"10.3390","volume":"23","author":[{"given":"Ryota","family":"Kirikoshi","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8866-0526","authenticated-orcid":false,"given":"Noriyoshi","family":"Manabe","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ohgi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1126\/science.279.5349.377","article-title":"Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model","volume":"279","author":"Arap","year":"1998","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/12469","article-title":"Anti-cancer activity of targeted pro-apoptotic peptides","volume":"5","author":"Ellerby","year":"1999","journal-title":"Nat. Med."},{"key":"ref_3","first-page":"722","article-title":"Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis","volume":"60","author":"Pasqualini","year":"2000","journal-title":"Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1038\/81183","article-title":"Enhancement of tumor necrosis factor \u03b1 antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13)","volume":"18","author":"Curnis","year":"2000","journal-title":"Nat. Biotechnol."},{"key":"ref_5","first-page":"867","article-title":"Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells","volume":"62","author":"Curnis","year":"2002","journal-title":"Cancer Res."},{"key":"ref_6","first-page":"7400","article-title":"Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy","volume":"63","author":"Pastorino","year":"2003","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7150","DOI":"10.1158\/0008-5472.CAN-04-1445","article-title":"Crucial role for interferon \u03b3 in the synergism between tumor vasculature-targeted tumor necrosis factor \u03b1 (NGR-TNF) and doxorubicin","volume":"64","author":"Sacchi","year":"2004","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1158\/0008-5472.CAN-04-4282","article-title":"Targeted delivery of IFN\u03b3 to tumor vessels uncouples antitumor from counterregulatory mechanisms","volume":"65","author":"Curnis","year":"2005","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10073","DOI":"10.1158\/0008-5472.CAN-06-2117","article-title":"Targeting liposomal chemotherapy via both tumor cell-specific and tumor vasculature-specific ligands potentiates therapeutic efficacy","volume":"66","author":"Pastorino","year":"2006","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7676","DOI":"10.1158\/0008-5472.CAN-08-0689","article-title":"Quantitative molecular magnetic resonance imaging of tumor angiogenesis using cNGR-labeled paramagnetic quantum dots","volume":"68","author":"Oostendorp","year":"2008","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5019","DOI":"10.1182\/blood-2008-04-150318","article-title":"Infarction of tumor vessels by NGR-peptide-directed targeting of tissue factor: Experimental results and first-in-man experience","volume":"113","author":"Bieker","year":"2009","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1038\/gt.2009.97","article-title":"Efficient delivery of angiostatin K1-5 into tumors following insertion of an NGR peptide into adenovirus capsid","volume":"16","author":"Jullienne","year":"2009","journal-title":"Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jconrel.2009.05.030","article-title":"NGR-modified micelles enhance their interaction with CD13-overexpressing tumor and endothelial cells","volume":"139","author":"Wang","year":"2009","journal-title":"J. Control. Release"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ejca.2009.10.005","article-title":"Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumors","volume":"46","author":"Gregorc","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.canlet.2009.06.008","article-title":"A novel DDS strategy, \u201cdual-targeting\u201d, and its application for antineovascular therapy","volume":"287","author":"Murase","year":"2010","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1158\/1078-0432.CCR-09-1621","article-title":"Phase I clinical and magnetic resonance imaging study of the vascular agent NGR-hTNF in patients with advanced cancers (European organization for research and treatment of cancer study 16041)","volume":"16","author":"Fiedler","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1200\/JCO.2009.27.3649","article-title":"Phase II study of asparagine-glycine-arginine\u2013human tumor necrosis factor \u03b1, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma","volume":"28","author":"Gregorc","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1016\/j.ejca.2010.07.012","article-title":"Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy","volume":"46","author":"Santoro","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1349-7006.2010.01826.x","article-title":"Aminopeptidase N (CD13) as a target for cancer chemotherapy","volume":"102","author":"Larsson","year":"2011","journal-title":"Cancer Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1158\/1078-0432.CCR-10-1376","article-title":"Phase I study of NGR-hTNF, a selective vascular targeting agent, in combination with cisplatin in refractory solid tumors","volume":"17","author":"Gregorc","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.yrtph.2011.02.007","article-title":"Anti-tumor efficacy and pre-clinical immunogenicity of IFN\u03b12a-NGR","volume":"60","author":"Zhang","year":"2011","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.2174\/138920111796117373","article-title":"Tumor vasculature targeting through NGR peptide-based drug delivery systems","volume":"12","author":"Corti","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jconrel.2011.05.022","article-title":"APN\/CD13-targeting as a strategy to alter the tumor accumulation of liposomes","volume":"154","author":"Dunne","year":"2011","journal-title":"J. Control. Release"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/bjc.2012.233","article-title":"Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients","volume":"107","author":"Lorusso","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1002\/med.20238","article-title":"Targeted drug delivery and penetration into solid tumors","volume":"32","author":"Corti","year":"2012","journal-title":"Med. Res. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1021\/co300055s","article-title":"NGR peptide ligands for targeting CD13\/APN identified through peptide array screening resemble fibronectin sequences","volume":"14","author":"Soudy","year":"2012","journal-title":"ACS Comb. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/bjc.2012.506","article-title":"Phase I and pharmacodynamic study of high-dose NGR\u2013hTNF in patients with refractory solid tumours","volume":"108","author":"Zucali","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s40259-013-0048-z","article-title":"Peptide-mediated targeting of cytokines to tumor vasculature: The NGR-hTNF example","volume":"27","author":"Corti","year":"2013","journal-title":"BioDrugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.jconrel.2013.06.015","article-title":"Enhanced anti-tumor and anti-angiogenic efficacy of a novel liposomal fenretinide on human neuroblastoma","volume":"170","author":"Pastorino","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_30","first-page":"1","article-title":"Vascular-homing peptides for targeted drug delivery and molecular imaging: Meeting the clinical challenges","volume":"1846","author":"Caraglia","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e963406","DOI":"10.4161\/21624011.2014.963406","article-title":"A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma","volume":"3","author":"Parmiani","year":"2014","journal-title":"OncoImmunology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"34520","DOI":"10.1074\/jbc.M114.566802","article-title":"A unified mechanism for aminopeptidase N-based tumor cell motility and tumor-homing therapy","volume":"289","author":"Liu","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jconrel.2015.05.286","article-title":"Tumor vascular targeted liposomal-bortezomib minimizes side effects and increases therapeutic activity in human neuroblastoma","volume":"211","author":"Zuccari","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1007\/s12274-016-1035-8","article-title":"NGR-tagged nano-gold: A new CD13-selective carrier for cytokine delivery to tumors","volume":"9","author":"Curnis","year":"2016","journal-title":"Nano Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mina-Osorio, P. (2017). Targeting CD13 with Asn-Gly-Arg (NGR) peptide-drug conjugates. Next-Generation Therapies and Technologies for Immene-Mediated Inflammatory Diseases, Springer.","DOI":"10.1007\/978-3-319-42252-7"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4348","DOI":"10.1039\/C7TB00318H","article-title":"Peptides for tumor-specific drug targeting: State of the art and beyond","volume":"5","author":"Roveri","year":"2017","journal-title":"J. Mater. Chem. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.1038\/s41388-018-0213-4","article-title":"NGR (Asn-Gly-Arg)-targetted delivery of coagulase to tumor vasculature arrests cancer cell growth","volume":"37","author":"Seidi","year":"2018","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0021-9258(19)75855-4","article-title":"Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation","volume":"262","author":"Geiger","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_39","first-page":"195","article-title":"Deamidation via cyclic imide in asparaginyl peptides","volume":"2","author":"Capasso","year":"1989","journal-title":"Pept. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6164","DOI":"10.1016\/S0021-9258(18)83327-0","article-title":"Succinimide formation from aspartyl and asparaginyl peptides as a model for the spontaneous degradation of proteins","volume":"264","author":"Stephenson","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1023\/A:1015807303766","article-title":"Chemical pathways of peptide degradation. II. Kinetics of deamidation of an asparaginyl residue in a model hexapeptide","volume":"7","author":"Patel","year":"1990","journal-title":"Pharm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1023\/A:1015999012852","article-title":"Chemical pathways of peptide degradation. III. Effect of primary sequence on the pathways of deamidation of asparaginyl residues in hexapeptides","volume":"7","author":"Patel","year":"1990","journal-title":"Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"22549","DOI":"10.1016\/S0021-9258(18)54607-X","article-title":"Effects of amino acid sequence, buffers, and ionic strength on the rate and mechanism of deamidation of asparagine residues in small peptides","volume":"266","author":"Schirch","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_44","unstructured":"Ahern, T.J., and Manning, M.C. (1992). Lability of asparagine and aspartic acid residues in proteins and peptides: Spontaneous deamidation and isomerization reactions. Stability of Protein Pharmaceuticals, Part A: Chemical and Physical Pathways of Protein Degradation, Plenum Press."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/j.1399-3011.2004.00151.x","article-title":"Structure-dependent nonenzymatic deamidation of glutaminyl and asparaginyl pentapeptides","volume":"63","author":"Robinson","year":"2004","journal-title":"J. Pept. Res."},{"key":"ref_46","unstructured":"Robinson, N.E., and Robinson, A.B. (2004). Molecular Clocks: Deamidation of Asparaginyl and Glutaminyl Residues in Peptides and Proteins, Althouse Press."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1021\/mp500011z","article-title":"Specific catalysis of asparaginyl deamidation by carboxylic acids: Kinetic, thermodynamic, and quantitative structure-property relationship analyses","volume":"11","author":"Connolly","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1021\/acschembio.7b00686","article-title":"Sequence and solution effects on the prevalence of d-isomers produced by deamidation","volume":"12","author":"Riggis","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7261","DOI":"10.3390\/ijms16047261","article-title":"Glycolic acid-catalyzed deamidation of asparagine residues in degrading PLGA matrices: A computational study","volume":"16","author":"Manabe","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Takahashi, O., Manabe, N., and Kirikoshi, R. (2016). A computational study of the mechanism of succinimide formation in the Asn\u2013His sequence: Intramolecular catalysis by the His side chain. Molecules, 21.","DOI":"10.3390\/molecules21030327"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.4236\/health.2013.512273","article-title":"Two-water-assisted racemization of the succinimide intermediate formed in proteins: A computational model study","volume":"5","author":"Takahashi","year":"2013","journal-title":"Health"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Takahashi, O., Kirikoshi, R., and Manabe, N. (2016). Racemization of the succinimide intermediate formed in proteins and peptides: A computational study of the mechanism catalyzed by dihydrogen phosphate ion. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101698"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"36466","DOI":"10.1074\/jbc.M604812200","article-title":"Spontaneous formation of l-isoaspartate and gain of function in fibronectin","volume":"281","author":"Curnis","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1182\/blood-2008-04-150862","article-title":"The neovasculature homing motif NGR: More than meets the eye","volume":"112","author":"Corti","year":"2008","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"9114","DOI":"10.1074\/jbc.M109.044297","article-title":"Critical role of flanking residues in NGR-to-isoDGR transition and CD13\/integrin receptor switching","volume":"285","author":"Curnis","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1242\/jcs.077172","article-title":"Isoaspartate-dependent molecular switches for integrin\u2013ligand recognition","volume":"124","author":"Corti","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/187152012800228751","article-title":"NGR-based strategies for targeting delivery of chemotherapeutics to tumor vasculature","volume":"12","author":"Zou","year":"2012","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1021\/jm501630j","article-title":"Development of cyclic NGR peptides with thioether linkage: Structure and dynamics determining deamidation and bioactivity","volume":"58","author":"Enyedi","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Enyedi, K.N., T\u00f3th, S., Szak\u00e1cs, G., and Mez\u0151, G. (2017). NGR-peptide\u2013drug conjugates with dual targeting properties. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178632"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5765","DOI":"10.1038\/s41598-017-06202-2","article-title":"Monocyte adhesion to atherosclerotic matrix proteins is enhanced by Asn-Gly-Arg deamidation","volume":"7","author":"Dutta","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"911","DOI":"10.3762\/bjoc.14.78","article-title":"Development of novel cyclic NGR peptide\u2013daunomycin conjugates with dual targeting property","volume":"14","author":"Tripodi","year":"2018","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cyto.2018.01.024","article-title":"A deamidated interferon-\u03b2 variant binds to integrin \u03b1v\u03b23","volume":"104","author":"Mastrangeli","year":"2018","journal-title":"Cytokine"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"19757","DOI":"10.1074\/jbc.M710273200","article-title":"Structural basis for the interaction of isoDGR with the RGD-binding site of \u03b1v\u03b23 integrin","volume":"283","author":"Spitaleri","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7073","DOI":"10.1158\/0008-5472.CAN-08-1272","article-title":"Isoaspartate-glycine-arginine: A new tumor vasculature-targeting motif","volume":"68","author":"Curnis","year":"2008","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1039\/C5BM00429B","article-title":"Systemic and tumor-targeted delivery of siRNA by cyclic NGR and isoDGR motif-containing peptides","volume":"4","author":"Huang","year":"2016","journal-title":"Biomater. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kirikoshi, R., Manabe, N., and Takahashi, O. (2018). Phosphate-catalyzed succinimide formation from Asp residues: A computational study of the mechanism. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020637"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Kirikoshi, R., Manabe, N., and Takahashi, O. (2017). Succinimide formation from an NGR-containing cyclic peptide: Computational evidence for catalytic roles of phosphate buffer and the arginine side chain. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020429"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.bpc.2007.03.009","article-title":"Ions in water: Characterizing the forces that control chemical processes and biological structure","volume":"128","author":"Collins","year":"2007","journal-title":"Biophys. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1021\/ct7001418","article-title":"Self-consistent reaction field model for aqueous and nonaqueous solutions based on accurate polarized partial charges","volume":"3","author":"Marenich","year":"2007","journal-title":"J. Chem. Theory Comput."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1021\/ar800019z","article-title":"A universal approach to solvation modeling","volume":"41","author":"Cramer","year":"2008","journal-title":"Acc. Chem. Res."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Takahashi, O., Kirikoshi, R., and Manabe, N. (2017). Racemization of serine residues catalyzed by dihydrogen phosphate ion: A computational study. Catalysts, 7.","DOI":"10.3390\/catal7120363"},{"key":"ref_72","unstructured":"(2014). Spartan \u201914, Wavefunction, Inc.. version 1.1.4."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/9\/2217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:22:27Z","timestamp":1760196147000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/9\/2217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,31]]},"references-count":72,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["molecules23092217"],"URL":"https:\/\/doi.org\/10.3390\/molecules23092217","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,31]]}}}