Predicting extreme p K a shifts in staphylococcal nuclease mutants with constant pH molecular dynamics
dc.contributor.author | Arthur, Evan J. | en_US |
dc.contributor.author | Yesselman, Joseph D. | en_US |
dc.contributor.author | Brooks, Charles L. III | |
dc.date.accessioned | 2011-12-05T18:32:48Z | |
dc.date.available | 2013-02-01T20:26:17Z | en_US |
dc.date.issued | 2011-12 | en_US |
dc.identifier.citation | Arthur, Evan J.; Yesselman, Joseph D.; Brooks, Charles L. III (2011). "Predicting extreme p K a shifts in staphylococcal nuclease mutants with constant pH molecular dynamics ." Proteins: Structure, Function, and Bioinformatics 79(12): 3276-3286. <http://hdl.handle.net/2027.42/88038> | en_US |
dc.identifier.issn | 0887-3585 | en_US |
dc.identifier.issn | 1097-0134 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/88038 | |
dc.description.abstract | Accurate computational methods of determining protein and nucleic acid p K a values are vital to understanding pH‐dependent processes in biological systems. In this article, we use the recently developed method constant pH molecular dynamics (CPHMD) to explore the calculation of highly perturbed p K a values in variants of staphylococcal nuclease (SNase). Simulations were performed using the replica exchange (REX) protocol for improved conformational sampling with eight temperature windows, and yielded converged proton populations in a total sampling time of 4 ns. Our REX‐CPHMD simulations resulted in calculated p K a values with an average unsigned error (AUE) of 0.75 pK units for the acidic residues in Δ + PHS, a hyperstable variant of SNase. For highly p K a ‐perturbed SNase mutants with known crystal structures, our calculations yielded an AUE of 1.5 pK units and for those mutants based on modeled structures an AUE of 1.4 pK units was found. Although a systematic underestimate of pK shifts was observed in most of the cases for the highly perturbed pK mutants, correlations between conformational rearrangement and plasticity associated with the mutation and error in p K a prediction was not evident in the data. This study further extends the scope of electrostatic environments explored using the REX‐CPHMD methodology and suggests that it is a reliable tool for rapidly characterizing ionizable amino acids within proteins even when modeled structures are employed. Proteins 2011; © 2011 Wiley‐Liss, Inc. | en_US |
dc.publisher | Wiley Subscription Services, Inc., A Wiley Company | en_US |
dc.subject.other | CPHMD | en_US |
dc.subject.other | Titration | en_US |
dc.subject.other | Molecular Dynamics | en_US |
dc.subject.other | Buried Charges | en_US |
dc.title | Predicting extreme p K a shifts in staphylococcal nuclease mutants with constant pH molecular dynamics | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Biological Chemistry | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109‐1055 | en_US |
dc.contributor.affiliationum | Biophysics Program, University of Michigan, Ann Arbor, Michigan 48109‐1055 | en_US |
dc.contributor.affiliationum | Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109‐1055 | en_US |
dc.identifier.pmid | 22002886 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/88038/1/23195_ftp.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/88038/2/PROT_23195_sm_SuppInfo.pdf | |
dc.identifier.doi | 10.1002/prot.23195 | en_US |
dc.identifier.source | Proteins: Structure, Function, and Bioinformatics | en_US |
dc.identifier.citedreference | Rastogi VK, Girvin ME. Structural changes linked to proton translocation by subunit c of the ATP synthase. Nature 1999; 402: 263 – 268. | en_US |
dc.identifier.citedreference | Ovchinnikov V, Trout BL, Karplus M. Mechanical coupling in myosin V: a simulation study. J Mol Biol 2010; 395: 815 – 833. | en_US |
dc.identifier.citedreference | Harris TK, Turner GJ. Structural basis of perturbed pK(a) values of catalytic groups in enzyme active sites. IUBMB Life 2002; 53: 85 – 98. | en_US |
dc.identifier.citedreference | Kelly JW. Alternative conformations of amyloidogenic proteins govern their behavior. Curr Opin Struct Biol 1996; 6: 11 – 17. | en_US |
dc.identifier.citedreference | Khandogin J, Brooks CL, III. Linking folding with aggregation in Alzheimer's beta‐amyloid peptides. Proc Natl Acad Sci U S A 2007; 104: 16880 – 16885. | en_US |
dc.identifier.citedreference | Khandogin J, Brooks CL, III. Constant pH molecular dynamics with proton tautomerism. Biophys J 2005; 89: 141 – 157. | en_US |
dc.identifier.citedreference | Khandogin J, Brooks CL, III. Toward the accurate first‐principles prediction of ionization equilibria in proteins. Biochemistry 2006; 45: 9363 – 9373. | en_US |
dc.identifier.citedreference | Wallace JA, Shen JK. Predicting pKa values with continuous constant pH molecular dynamics. Methods Enzymol 2009; 466: 455 – 475. | en_US |
dc.identifier.citedreference | Thurlkill RL, Grimsley GR, Scholtz JM, Pace CN. pK values of the ionizable groups of proteins. Protein Sci 2006; 15: 1214 – 1218. | en_US |
dc.identifier.citedreference | Bas DC, Rogers DM, Jensen JH. Very fast prediction and rationalization of pK(a) values for protein‐ligand complexes. Proteins 2008; 73: 765 – 783. | en_US |
dc.identifier.citedreference | Li H, Robertson AD, Jensen JH. Very fast empirical prediction and rationalization of protein pKa values. Proteins 2005; 61: 704 – 721. | en_US |
dc.identifier.citedreference | Alexov EG, Gunner MR. Incorporating protein conformational flexibility into the calculation of pH‐dependent protein properties. Biophys J 1997; 72: 2075 – 2093. | en_US |
dc.identifier.citedreference | Georgescu RE, Alexov EG, Gunner MR. Combining conformational flexibility and continuum electrostatics for calculating pK(a)s in proteins. Biophys J 2002; 83: 1731 – 1748. | en_US |
dc.identifier.citedreference | Bashford D, Gerwert K. Electrostatic calculations of the pKa values of ionizable groups in bacteriorhodopsin. J Mol Biol 1992; 224 473 – 486. | en_US |
dc.identifier.citedreference | Bashford D. An object‐oriented programming suite for electrostatic effects in biological molecules: an experience report on the MEAD project. In: Ishikawa Y, Oldehoeft R, Reynders J, Tholburn M, editors. Scientific computing in object‐oriented parallel environments, Vol. 1343, Lecture Notes in Computer Science: Springer Berlin/Heidelberg; 1997. pp 233 – 240. | en_US |
dc.identifier.citedreference | Bashford D. Macroscopic electrostatic models for protonation states in proteins. Front Biosci 2004; 9: 1082 – 1099. | en_US |
dc.identifier.citedreference | Baptista AM, Teixeira VH, Soares CM. Constant‐pH molecular dynamics using stochastic titration. J Chem Phys 2002; 117: 4184 – 4200. | en_US |
dc.identifier.citedreference | Mongan JT, Case DA, McCammon JA. Constant pH molecular dynamics in generalized born implicit solvent. Abstr Pap Am Chem Soc 2005; 229: U768. | en_US |
dc.identifier.citedreference | Kannan S, Zacharias M. Enhanced sampling of peptide and protein conformations using replica exchange simulations with a peptide backbone biasing‐potential. Proteins 2007; 66: 697 – 706. | en_US |
dc.identifier.citedreference | Lee MS, Salsbury FR, Brooks CL, III. Constant‐pH molecular dynamics using continuous titration coordinates. Proteins 2004; 56: 738 – 752. | en_US |
dc.identifier.citedreference | Brooks BR, Brooks CL, III, Mackerell AD, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M. CHARMM: the biomolecular simulation program. J Comput Chem 2009; 30: 1545 – 1614. | en_US |
dc.identifier.citedreference | Knight JL, Brooks CL, III. λ‐Dynamics free energy simulation methods. J Comput Chem 2009; 30: 1692 – 1700. | en_US |
dc.identifier.citedreference | Kong XJ, Brooks CL, III. Lambda‐dynamics: a new approach to free energy calculations. J Chem Phys 1996; 105: 2414 – 2423. | en_US |
dc.identifier.citedreference | Im W, Lee MS, Brooks CL, III. Generalized born model with a simple smoothing function. J Comput Chem 2003; 24: 1691 – 1702. | en_US |
dc.identifier.citedreference | Chen J, Brooks CL, III, Khandogin J. Recent advances in implicit solvent‐based methods for biomolecular simulations. Curr Opin Struct Biol 2008; 18: 140 – 148. | en_US |
dc.identifier.citedreference | Nose S. A unified formulation of the constant temperature molecular‐dynamics methods. J Chem Phys 1984; 81: 511 – 519. | en_US |
dc.identifier.citedreference | Isom DG, Castañeda CA, Cannon BR, Velu PD, García‐Moreno EB. Charges in the hydrophobic interior of proteins. Proc Natl Acad Sci 2010; 107: 16096 – 16100. | en_US |
dc.identifier.citedreference | Arata Y, Khalifah R, Jardetzky O. NMR relaxation studies of unfolding and refolding of staphylococcal nuclease at low pH. Ann NY Acad Sci 1973; 222: 230 – 239. | en_US |
dc.identifier.citedreference | Erickson A, Deibel RH. Production and heat‐stability of staphylococcal nuclease. J Appl Microbiol 1973; 25: 332 – 336. | en_US |
dc.identifier.citedreference | Castaneda CA, Fitch CA, Majumdar A, Khangulov V, Schlessman JL, Garcia‐Moreno BE. Molecular determinants of the pK(a) values of Asp and Glu residues in staphylococcal nuclease. Proteins 2009; 77: 570 – 588. | en_US |
dc.identifier.citedreference | Baran K, Fitch C, Schlessman J, Garcia‐Moreno B. Molecular determinants of pKa values of ionizable residues involved in clusters and networks: contributions by short‐range interactions and by local conformational fluctuations. Biophys J 2005; 88: 38A. | en_US |
dc.identifier.citedreference | Cannon B, Isom D, Robinson A, Seedorff J, Garcia‐Moreno B. Molecular determinants of the pKa values of the internal Asp residues. Biophys J 2007: 403A. | en_US |
dc.identifier.citedreference | Karp DA, Gittis AG, Stahley MR, Fitch CA, Stites WE, Garcia‐Moreno B. High apparent dielectric constant inside a protein reflects structural reorganization coupled to the ionization of an internal Asp. Biophys J 2007; 92: 2041 – 2053. | en_US |
dc.identifier.citedreference | Sugita Y, Okamoto Y. Replica‐exchange molecular dynamics method for protein folding. Chem Phys Lett 1999; 314: 141 – 151. | en_US |
dc.identifier.citedreference | Feig M, Karanicolas J, Brooks CL, III. MMTSB tool set: enhanced sampling and multiscale modeling methods for applications in structural biology. J Mol Graph Model 2004; 22: 377 – 395. | en_US |
dc.identifier.citedreference | Hess B, Kutzner C, van der Spoel D, Lindahl E. GROMACS 4: algorithms for highly efficient, load‐balanced, and scalable molecular simulation. J Chem Theory Comput 2008; 4: 435 – 447. | en_US |
dc.identifier.citedreference | Chen JH, Im WP, Brooks CL, III. Balancing solvation and intramolecular interactions: toward a consistent generalized born force field. J Am Chem Soc 2006; 128: 3728 – 3736. | en_US |
dc.identifier.citedreference | Tsui V, Case DA. Theory and applications of the generalized Born solvation model in macromolecular simulations. Biopolymers 2000; 56: 275 – 291. | en_US |
dc.identifier.citedreference | Bashford D, Case DA. Generalized born models of macromolecular solvation effects. Annu Rev Phys Chem 2000; 51: 129 – 152. | en_US |
dc.identifier.citedreference | MacKerell AD, Bashford D, Bellott M, Dunbrack RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph‐McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz‐Kuczera J, Yin D, Karplus M. All‐atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 1998; 102: 3586 – 3616. | en_US |
dc.identifier.citedreference | Feig M, MacKerell AD, Brooks CL, III. Force field influence on the observation of pi‐helical protein structures in molecular dynamics simulations. J Phys Chem B 2003; 107: 2831 – 2836. | en_US |
dc.identifier.citedreference | Sitkoff D, Sharp KA, Honig B. Accurate calculation of hydration free‐energies using macroscopic solvent models. J Phys Chem 1994; 98: 1978 – 1988. | en_US |
dc.identifier.citedreference | Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The Protein Data Bank. Nucleic Acids Res 2000; 28: 235 – 242. | en_US |
dc.identifier.citedreference | Wallace JA, Wang Y, Shi C, Pastoor KJ, Nguyen B‐L, Xia K, Shen JK. Toward accurate prediction of pKa values for internal protein residues: the importance of conformational relaxation and desolvation energy. Proteins 2011; 79: 3364 – 3373. | en_US |
dc.identifier.citedreference | Fitch CA, Whitten ST, Hilser VJ, Garcia‐Moreno EB. Molecular mechanisms of pH‐driven conformational transitions of proteins: insights from continuum electrostatics calculations of acid unfolding. Proteins 2006; 63: 113 – 126. | en_US |
dc.identifier.citedreference | Creighton TE. Proteins: Structure and Molecular Properties: WH Freeman & Co; 2011. | en_US |
dc.identifier.citedreference | Chimenti MS, Castaneda CA, Majumdar A, Garcia‐Moreno EB. Structural origins of high apparent dielectric constants experienced by ionizable groups in the hydrophobic core of a protein. J Mol Biol 2011; 405: 361 – 377. | en_US |
dc.identifier.citedreference | Garcia‐Moreno B, Dwyer JJ, Gittis AG, Lattman EE, Spencer DS, Stites WE. Experimental measurement of the effective dielectric in the hydrophobic core of a protein. Biophys Chem 1997; 64: 211 – 224. | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.