DOI: 10.1126/science.2727695. Hidden Thermodynamics of Mutant Proteins: A Molecular Dynamics Analysis

Hidden Thermodynamics of Mutant Proteins: A Molecular Dynamics Analysis

10.1126/science.2727695

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

A molecular dynamics simulation method is used to determine the contributions of individual amino acid residues and solvent molecules to free energy changes in proteins. Its application to the hemoglobin interface mutant Asp G1(99) β→Ala shows that some of the contributions to the difference in the free energy of cooperativity are as large as 60 kilocalories (kcal) per mole. Since the overall free energy change is only -5.5 kcal/mole (versus the experimental value of -3.4 kcal/mole), essential elements of the thermodynamics are hidden in the measured results. By exposing the individual contributions, the free energy simulation provides new insights into the origin of thermodynamic changes in mutant proteins and demonstrates the role of effects beyond those usually considered in structural analyses.

Bibliography

Gao, J., Kuczera, K., Tidor, B., & Karplus, M. (1989). Hidden Thermodynamics of Mutant Proteins: A Molecular Dynamics Analysis. Science, 244(4908), 1069â1072.

Authors 4

Jiali Gao (first)
Krzysztof Kuczera (additional)
Bruce Tidor (additional)
Martin Karplus (additional)

References 41 Referenced 239

ACKERS G.K. COMMUNICATION.
ALBER, T, CONTRIBUTIONS OF HYDROGEN-BONDS OF THR-157 TO THE THERMODYNAMIC STABILITY OF PHAGE-T4 LYSOZYME, NATURE 330: 41 (1987). (10.1038/330041a0) / NATURE (1987)
BALDWIN, J, HEMOGLOBIN - STRUCTURAL-CHANGES RELATED TO LIGAND-BINDING AND ITS ALLOSTERIC MECHANISM, JOURNAL OF MOLECULAR BIOLOGY 129: 175 (1979). (10.1016/0022-2836(79)90277-8) / JOURNAL OF MOLECULAR BIOLOGY (1979)
10.1126/science.3810157
BASHFORD, D, ELECTROSTATIC EFFECTS OF CHARGE PERTURBATIONS INTRODUCED BY METAL OXIDATION IN PROTEINS - A THEORETICAL-ANALYSIS, JOURNAL OF MOLECULAR BIOLOGY 203: 507 (1988). (10.1016/0022-2836(88)90016-2) / JOURNAL OF MOLECULAR BIOLOGY (1988)
BENNAIM, A, SOLVATION THERMODYNAMICS OF NONIONIC SOLUTES, JOURNAL OF CHEMICAL PHYSICS 81: 2016 (1984). (10.1063/1.447824) / JOURNAL OF CHEMICAL PHYSICS (1984)
BROOKS, B.R., CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS, JOURNAL OF COMPUTATIONAL CHEMISTRY 4: 187 (1983). (10.1002/jcc.540040211) / JOURNAL OF COMPUTATIONAL CHEMISTRY (1983)
Brooks C. L. Proteins: A Theoretical Perspective of Dynamics Structure and Thermodynamics (1988).
BRUNGER, A.T., ACTIVE-SITE DYNAMICS OF RIBONUCLEASE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 82: 8458 (1985). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1985)
Bunn H. F. Hemoglobin: Molecular Genetic Clinical Aspects (1980).
Dickerson R. E. Hemoglobin: Structure Function Evolution and Pathology (1983).
FERMI, G, THE CRYSTAL-STRUCTURE OF HUMAN DEOXYHEMOGLOBIN AT 1.74A RESOLUTION, JOURNAL OF MOLECULAR BIOLOGY 175: 159 (1984). (10.1016/0022-2836(84)90472-8) / JOURNAL OF MOLECULAR BIOLOGY (1984)
FERSHT, A.R., THE HYDROGEN-BOND IN MOLECULAR RECOGNITION, TRENDS IN BIOCHEMICAL SCIENCES 12: 301 (1987). (10.1016/0968-0004(87)90146-0) / TRENDS IN BIOCHEMICAL SCIENCES (1987)
FLEISCHMAN S.H. unpublished data.
GAO, J, ABINITIO STUDY OF STRUCTURES AND BINDING-ENERGIES FOR ANION WATER COMPLEXES, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 108: 4784 (1986). (10.1021/ja00276a016) / JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (1986)
GELIN, B.R., HEMOGLOBIN TERTIARY STRUCTURAL-CHANGE ON LIGAND-BINDING - ITS ROLE IN THE CO-OPERATIVE MECHANISM, JOURNAL OF MOLECULAR BIOLOGY 171: 489 (1983). (10.1016/0022-2836(83)90042-6) / JOURNAL OF MOLECULAR BIOLOGY (1983)
GILSON, M.K., CALCULATION OF ELECTROSTATIC POTENTIALS IN AN ENZYME ACTIVE-SITE, NATURE 330: 84 (1987). (10.1038/330084a0) / NATURE (1987)
JORGENSEN, W.L., COMPARISON OF SIMPLE POTENTIAL FUNCTIONS FOR SIMULATING LIQUID WATER, JOURNAL OF CHEMICAL PHYSICS 79: 926 (1983). (10.1063/1.445869) / JOURNAL OF CHEMICAL PHYSICS (1983)
JORGENSEN, W.L., MONTE-CARLO SIMULATION OF DIFFERENCES IN FREE-ENERGIES OF HYDRATION, JOURNAL OF CHEMICAL PHYSICS 83: 3050 (1985). (10.1063/1.449208) / JOURNAL OF CHEMICAL PHYSICS (1985)
KIRKWOOD, J.G., Statistical mechanics of fluid mixtures, JOURNAL OF CHEMICAL PHYSICS 3: 300 (1935). (10.1063/1.1749657) / JOURNAL OF CHEMICAL PHYSICS (1935)
KIRKWOOD, J.G., The radial distribution function in liquids, JOURNAL OF CHEMICAL PHYSICS 10: 394 (1942). (10.1063/1.1723737) / JOURNAL OF CHEMICAL PHYSICS (1942)
KUCZERA K unpublished data.
LEE, B, INTERPRETATION OF PROTEIN STRUCTURES - ESTIMATION OF STATIC ACCESSIBILITY, JOURNAL OF MOLECULAR BIOLOGY 55: 379 (1971). (10.1016/0022-2836(71)90324-X) / JOURNAL OF MOLECULAR BIOLOGY (1971)
MEOTNER, M, IONIC HYDROGEN-BOND AND ION SOLVATION .6. INTERACTION ENERGIES OF THE ACETATE ION WITH ORGANIC-MOLECULES - COMPARISON OF CH3COO- WITH CL-, CN-, AND SH-, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 110: 3854 (1988). (10.1021/ja00220a021) / JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (1988)
MEZEI, M, EXCESS FREE-ENERGY OF DIFFERENT WATER MODELS COMPUTED BY MONTE-CARLO METHODS, MOLECULAR PHYSICS 47: 1307 (1982). (10.1080/00268978200100992) / MOLECULAR PHYSICS (1982)
PEARSON, R.G., IONIZATION-POTENTIALS AND ELECTRON-AFFINITIES IN AQUEOUS-SOLUTION, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 108: 6109 (1986). (10.1021/ja00280a002) / JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (1986)
PERUTZ, M.F., STEREOCHEMISTRY OF COOPERATIVE MECHANISMS IN HEMOGLOBIN, ACCOUNTS OF CHEMICAL RESEARCH 20: 309 (1987). (10.1021/ar00141a001) / ACCOUNTS OF CHEMICAL RESEARCH (1987)
Perutz M. F. Haemoglobin and Myoglobin Atlas of Molecular Structures in Biology 2 (1981).
PERUTZ, M.F., STEREOCHEMISTRY OF COOPERATIVE EFFECTS IN HAEMOGLOBIN, NATURE 228: 726 (1970). (10.1038/228726a0) / NATURE (1970)
PERUTZ, M, NATURE 232: 408 (1971). (10.1038/232408a0) / NATURE (1971)
Pettigrew, D. W., Proceedings of the National Academy of Sciences of the United States of America 79: 1849 (1982). / Proceedings of the National Academy of Sciences of the United States of America (1982)
Pettit, B. M., Molecular Graphics and Drug Design: 75 (1986). / Molecular Graphics and Drug Design (1986)
POSTMA, J. P. M., FARADAY SYMPOSIA OF THE CHEMICAL SOCIETY 17: 55 (1982). (10.1039/fs9821700055) / FARADAY SYMPOSIA OF THE CHEMICAL SOCIETY (1982)
PULSINELLI, P.D., STRUCTURE OF DEOXYHEMOGLOBIN YAKIMA - HIGH-AFFINITY MUTANT FORM EXHIBITING OXY-LIKE ALPHA1 BETA2 SUBUNIT INTERACTIONS, JOURNAL OF MOLECULAR BIOLOGY 74: 57 (1973). (10.1016/0022-2836(73)90354-9) / JOURNAL OF MOLECULAR BIOLOGY (1973)
SHAANAN, B, STRUCTURE OF HUMAN OXYHEMOGLOBIN AT 2.1 A RESOLUTION, JOURNAL OF MOLECULAR BIOLOGY 171: 31 (1983). (10.1016/S0022-2836(83)80313-1) / JOURNAL OF MOLECULAR BIOLOGY (1983)
SHIH, HHL, STRUCTURE OF PROTEINS WITH SINGLE-SITE MUTATIONS - A MINIMUM PERTURBATION APPROACH, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 82: 1697 (1985). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1985)
TEMBE, B.L., LIGAND RECEPTOR INTERACTIONS, COMPUTERS & CHEMISTRY 8: 281 (1984). (10.1016/0097-8485(84)85020-2) / COMPUTERS & CHEMISTRY (1984)
WEATHERALL, D.J., HEMOGLOBIN RADCLIFFE (ALPHA-2 BETA-2 99(GI)ALA) - HIGH OXYGEN-AFFINITY VARIANT CAUSING FAMILIAL POLYCYTHEMIA, BRITISH JOURNAL OF HAEMATOLOGY 35: 177 (1977). (10.1111/j.1365-2141.1977.tb00575.x) / BRITISH JOURNAL OF HAEMATOLOGY (1977)
WISHNER, B.C., CRYSTAL-STRUCTURE OF SICKLE-CELL DEOXYHEMOGLOBIN AT 5 A RESOLUTION, JOURNAL OF MOLECULAR BIOLOGY 98: 179 (1975). (10.1016/S0022-2836(75)80108-2) / JOURNAL OF MOLECULAR BIOLOGY (1975)
YU, H.A., A THERMODYNAMIC ANALYSIS OF SOLVATION, JOURNAL OF CHEMICAL PHYSICS 89: 2366 (1988). (10.1063/1.455080) / JOURNAL OF CHEMICAL PHYSICS (1988)
YU H unpublished data.

Dates

Type	When
Created	18 years, 10 months ago (Oct. 5, 2006, 5:21 p.m.)
Deposited	1 year, 7 months ago (Jan. 12, 2024, 11:27 p.m.)
Indexed	2 weeks, 6 days ago (Aug. 5, 2025, 8:53 a.m.)
Issued	36 years, 2 months ago (June 2, 1989)
Published	36 years, 2 months ago (June 2, 1989)
Published Print	36 years, 2 months ago (June 2, 1989)

Funders 0

None

BibTeX

@article{Gao_1989, title={Hidden Thermodynamics of Mutant Proteins: A Molecular Dynamics Analysis}, volume={244}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.2727695}, DOI={10.1126/science.2727695}, number={4908}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Gao, Jiali and Kuczera, Krzysztof and Tidor, Bruce and Karplus, Martin}, year={1989}, month=jun, pages={1069–1072} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        5
      ]
    ],
    "date-time": "2025-08-05T12:53:59Z",
    "timestamp": 1754398439201
  },
  "reference-count": 41,
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "issue": "4908",
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        1989,
        6,
        2
      ]
    ]
  },
  "abstract": "<jats:p>A molecular dynamics simulation method is used to determine the contributions of individual amino acid residues and solvent molecules to free energy changes in proteins. Its application to the hemoglobin interface mutant Asp G1(99) \u03b2\u2192Ala shows that some of the contributions to the difference in the free energy of cooperativity are as large as 60 kilocalories (kcal) per mole. Since the overall free energy change is only -5.5 kcal/mole (versus the experimental value of -3.4 kcal/mole), essential elements of the thermodynamics are hidden in the measured results. By exposing the individual contributions, the free energy simulation provides new insights into the origin of thermodynamic changes in mutant proteins and demonstrates the role of effects beyond those usually considered in structural analyses.</jats:p>",
  "DOI": "10.1126/science.2727695",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2006,
        10,
        5
      ]
    ],
    "date-time": "2006-10-05T21:21:28Z",
    "timestamp": 1160083288000
  },
  "page": "1069-1072",
  "source": "Crossref",
  "is-referenced-by-count": 239,
  "title": "Hidden Thermodynamics of Mutant Proteins: A Molecular Dynamics Analysis",
  "prefix": "10.1126",
  "volume": "244",
  "author": [
    {
      "given": "Jiali",
      "family": "Gao",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Department of Chemistry, Harvard University, Cambridge, MA 02138."
        }
      ]
    },
    {
      "given": "Krzysztof",
      "family": "Kuczera",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, Harvard University, Cambridge, MA 02138."
        }
      ]
    },
    {
      "given": "Bruce",
      "family": "Tidor",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, Harvard University, Cambridge, MA 02138."
        }
      ]
    },
    {
      "given": "Martin",
      "family": "Karplus",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, Harvard University, Cambridge, MA 02138."
        }
      ]
    }
  ],
  "member": "221",
  "reference": [
    {
      "key": "e_1_2_1_1_1",
      "unstructured": "ACKERS G.K. COMMUNICATION."
    },
    {
      "key": "e_1_2_1_2_1",
      "doi-asserted-by": "crossref",
      "first-page": "41",
      "DOI": "10.1038/330041a0",
      "volume": "330",
      "year": "1987",
      "unstructured": "ALBER, T, CONTRIBUTIONS OF HYDROGEN-BONDS OF THR-157 TO THE THERMODYNAMIC STABILITY OF PHAGE-T4 LYSOZYME, NATURE 330: 41 (1987).",
      "journal-title": "NATURE"
    },
    {
      "key": "e_1_2_1_3_1",
      "doi-asserted-by": "crossref",
      "first-page": "175",
      "DOI": "10.1016/0022-2836(79)90277-8",
      "volume": "129",
      "year": "1979",
      "unstructured": "BALDWIN, J, HEMOGLOBIN - STRUCTURAL-CHANGES RELATED TO LIGAND-BINDING AND ITS ALLOSTERIC MECHANISM, JOURNAL OF MOLECULAR BIOLOGY 129: 175 (1979).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_4_1",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.3810157"
    },
    {
      "key": "e_1_2_1_5_1",
      "doi-asserted-by": "crossref",
      "first-page": "507",
      "DOI": "10.1016/0022-2836(88)90016-2",
      "volume": "203",
      "year": "1988",
      "unstructured": "BASHFORD, D, ELECTROSTATIC EFFECTS OF CHARGE PERTURBATIONS INTRODUCED BY METAL OXIDATION IN PROTEINS - A THEORETICAL-ANALYSIS, JOURNAL OF MOLECULAR BIOLOGY 203: 507 (1988).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_6_1",
      "doi-asserted-by": "crossref",
      "first-page": "2016",
      "DOI": "10.1063/1.447824",
      "volume": "81",
      "year": "1984",
      "unstructured": "BENNAIM, A, SOLVATION THERMODYNAMICS OF NONIONIC SOLUTES, JOURNAL OF CHEMICAL PHYSICS 81: 2016 (1984).",
      "journal-title": "JOURNAL OF CHEMICAL PHYSICS"
    },
    {
      "key": "e_1_2_1_7_1",
      "doi-asserted-by": "crossref",
      "first-page": "187",
      "DOI": "10.1002/jcc.540040211",
      "volume": "4",
      "year": "1983",
      "unstructured": "BROOKS, B.R., CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS, JOURNAL OF COMPUTATIONAL CHEMISTRY 4: 187 (1983).",
      "journal-title": "JOURNAL OF COMPUTATIONAL CHEMISTRY"
    },
    {
      "key": "e_1_2_1_8_1",
      "unstructured": "Brooks C. L. Proteins: A Theoretical Perspective of Dynamics Structure and Thermodynamics (1988)."
    },
    {
      "key": "e_1_2_1_9_1",
      "first-page": "8458",
      "volume": "82",
      "year": "1985",
      "unstructured": "BRUNGER, A.T., ACTIVE-SITE DYNAMICS OF RIBONUCLEASE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 82: 8458 (1985).",
      "journal-title": "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA"
    },
    {
      "key": "e_1_2_1_10_1",
      "unstructured": "Bunn H. F. Hemoglobin: Molecular Genetic Clinical Aspects (1980)."
    },
    {
      "key": "e_1_2_1_11_1",
      "unstructured": "Dickerson R. E. Hemoglobin: Structure Function Evolution and Pathology (1983)."
    },
    {
      "key": "e_1_2_1_12_1",
      "doi-asserted-by": "crossref",
      "first-page": "159",
      "DOI": "10.1016/0022-2836(84)90472-8",
      "volume": "175",
      "year": "1984",
      "unstructured": "FERMI, G, THE CRYSTAL-STRUCTURE OF HUMAN DEOXYHEMOGLOBIN AT 1.74A RESOLUTION, JOURNAL OF MOLECULAR BIOLOGY 175: 159 (1984).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_13_1",
      "doi-asserted-by": "crossref",
      "first-page": "301",
      "DOI": "10.1016/0968-0004(87)90146-0",
      "volume": "12",
      "year": "1987",
      "unstructured": "FERSHT, A.R., THE HYDROGEN-BOND IN MOLECULAR RECOGNITION, TRENDS IN BIOCHEMICAL SCIENCES 12: 301 (1987).",
      "journal-title": "TRENDS IN BIOCHEMICAL SCIENCES"
    },
    {
      "key": "e_1_2_1_14_1",
      "unstructured": "FLEISCHMAN S.H. unpublished data."
    },
    {
      "key": "e_1_2_1_15_1",
      "doi-asserted-by": "crossref",
      "first-page": "4784",
      "DOI": "10.1021/ja00276a016",
      "volume": "108",
      "year": "1986",
      "unstructured": "GAO, J, ABINITIO STUDY OF STRUCTURES AND BINDING-ENERGIES FOR ANION WATER COMPLEXES, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 108: 4784 (1986).",
      "journal-title": "JOURNAL OF THE AMERICAN CHEMICAL SOCIETY"
    },
    {
      "key": "e_1_2_1_16_1",
      "doi-asserted-by": "crossref",
      "first-page": "489",
      "DOI": "10.1016/0022-2836(83)90042-6",
      "volume": "171",
      "year": "1983",
      "unstructured": "GELIN, B.R., HEMOGLOBIN TERTIARY STRUCTURAL-CHANGE ON LIGAND-BINDING - ITS ROLE IN THE CO-OPERATIVE MECHANISM, JOURNAL OF MOLECULAR BIOLOGY 171: 489 (1983).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_17_1",
      "doi-asserted-by": "crossref",
      "first-page": "84",
      "DOI": "10.1038/330084a0",
      "volume": "330",
      "year": "1987",
      "unstructured": "GILSON, M.K., CALCULATION OF ELECTROSTATIC POTENTIALS IN AN ENZYME ACTIVE-SITE, NATURE 330: 84 (1987).",
      "journal-title": "NATURE"
    },
    {
      "key": "e_1_2_1_18_1",
      "doi-asserted-by": "crossref",
      "first-page": "926",
      "DOI": "10.1063/1.445869",
      "volume": "79",
      "year": "1983",
      "unstructured": "JORGENSEN, W.L., COMPARISON OF SIMPLE POTENTIAL FUNCTIONS FOR SIMULATING LIQUID WATER, JOURNAL OF CHEMICAL PHYSICS 79: 926 (1983).",
      "journal-title": "JOURNAL OF CHEMICAL PHYSICS"
    },
    {
      "key": "e_1_2_1_19_1",
      "doi-asserted-by": "crossref",
      "first-page": "3050",
      "DOI": "10.1063/1.449208",
      "volume": "83",
      "year": "1985",
      "unstructured": "JORGENSEN, W.L., MONTE-CARLO SIMULATION OF DIFFERENCES IN FREE-ENERGIES OF HYDRATION, JOURNAL OF CHEMICAL PHYSICS 83: 3050 (1985).",
      "journal-title": "JOURNAL OF CHEMICAL PHYSICS"
    },
    {
      "key": "e_1_2_1_20_1",
      "doi-asserted-by": "crossref",
      "first-page": "300",
      "DOI": "10.1063/1.1749657",
      "volume": "3",
      "year": "1935",
      "unstructured": "KIRKWOOD, J.G., Statistical mechanics of fluid mixtures, JOURNAL OF CHEMICAL PHYSICS 3: 300 (1935).",
      "journal-title": "JOURNAL OF CHEMICAL PHYSICS"
    },
    {
      "key": "e_1_2_1_21_1",
      "doi-asserted-by": "crossref",
      "first-page": "394",
      "DOI": "10.1063/1.1723737",
      "volume": "10",
      "year": "1942",
      "unstructured": "KIRKWOOD, J.G., The radial distribution function in liquids, JOURNAL OF CHEMICAL PHYSICS 10: 394 (1942).",
      "journal-title": "JOURNAL OF CHEMICAL PHYSICS"
    },
    {
      "key": "e_1_2_1_22_1",
      "unstructured": "KUCZERA K unpublished data."
    },
    {
      "key": "e_1_2_1_23_1",
      "doi-asserted-by": "crossref",
      "first-page": "379",
      "DOI": "10.1016/0022-2836(71)90324-X",
      "volume": "55",
      "year": "1971",
      "unstructured": "LEE, B, INTERPRETATION OF PROTEIN STRUCTURES - ESTIMATION OF STATIC ACCESSIBILITY, JOURNAL OF MOLECULAR BIOLOGY 55: 379 (1971).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_24_1",
      "doi-asserted-by": "crossref",
      "first-page": "3854",
      "DOI": "10.1021/ja00220a021",
      "volume": "110",
      "year": "1988",
      "unstructured": "MEOTNER, M, IONIC HYDROGEN-BOND AND ION SOLVATION .6. INTERACTION ENERGIES OF THE ACETATE ION WITH ORGANIC-MOLECULES - COMPARISON OF CH3COO- WITH CL-, CN-, AND SH-, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 110: 3854 (1988).",
      "journal-title": "JOURNAL OF THE AMERICAN CHEMICAL SOCIETY"
    },
    {
      "key": "e_1_2_1_25_1",
      "doi-asserted-by": "crossref",
      "first-page": "1307",
      "DOI": "10.1080/00268978200100992",
      "volume": "47",
      "year": "1982",
      "unstructured": "MEZEI, M, EXCESS FREE-ENERGY OF DIFFERENT WATER MODELS COMPUTED BY MONTE-CARLO METHODS, MOLECULAR PHYSICS 47: 1307 (1982).",
      "journal-title": "MOLECULAR PHYSICS"
    },
    {
      "key": "e_1_2_1_26_1",
      "doi-asserted-by": "crossref",
      "first-page": "6109",
      "DOI": "10.1021/ja00280a002",
      "volume": "108",
      "year": "1986",
      "unstructured": "PEARSON, R.G., IONIZATION-POTENTIALS AND ELECTRON-AFFINITIES IN AQUEOUS-SOLUTION, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 108: 6109 (1986).",
      "journal-title": "JOURNAL OF THE AMERICAN CHEMICAL SOCIETY"
    },
    {
      "key": "e_1_2_1_27_1",
      "doi-asserted-by": "crossref",
      "first-page": "309",
      "DOI": "10.1021/ar00141a001",
      "volume": "20",
      "year": "1987",
      "unstructured": "PERUTZ, M.F., STEREOCHEMISTRY OF COOPERATIVE MECHANISMS IN HEMOGLOBIN, ACCOUNTS OF CHEMICAL RESEARCH 20: 309 (1987).",
      "journal-title": "ACCOUNTS OF CHEMICAL RESEARCH"
    },
    {
      "key": "e_1_2_1_28_1",
      "unstructured": "Perutz M. F. Haemoglobin and Myoglobin Atlas of Molecular Structures in Biology 2 (1981)."
    },
    {
      "key": "e_1_2_1_29_1",
      "doi-asserted-by": "crossref",
      "first-page": "726",
      "DOI": "10.1038/228726a0",
      "volume": "228",
      "year": "1970",
      "unstructured": "PERUTZ, M.F., STEREOCHEMISTRY OF COOPERATIVE EFFECTS IN HAEMOGLOBIN, NATURE 228: 726 (1970).",
      "journal-title": "NATURE"
    },
    {
      "key": "e_1_2_1_30_1",
      "doi-asserted-by": "crossref",
      "first-page": "408",
      "DOI": "10.1038/232408a0",
      "volume": "232",
      "year": "1971",
      "unstructured": "PERUTZ, M, NATURE 232: 408 (1971).",
      "journal-title": "NATURE"
    },
    {
      "key": "e_1_2_1_31_1",
      "first-page": "1849",
      "volume": "79",
      "year": "1982",
      "unstructured": "Pettigrew, D. W., Proceedings of the National Academy of Sciences of the United States of America 79: 1849 (1982).",
      "journal-title": "Proceedings of the National Academy of Sciences of the United States of America"
    },
    {
      "key": "e_1_2_1_32_1",
      "first-page": "75",
      "year": "1986",
      "unstructured": "Pettit, B. M., Molecular Graphics and Drug Design: 75 (1986).",
      "journal-title": "Molecular Graphics and Drug Design"
    },
    {
      "key": "e_1_2_1_33_1",
      "doi-asserted-by": "crossref",
      "first-page": "55",
      "DOI": "10.1039/fs9821700055",
      "volume": "17",
      "year": "1982",
      "unstructured": "POSTMA, J. P. M., FARADAY SYMPOSIA OF THE CHEMICAL SOCIETY 17: 55 (1982).",
      "journal-title": "FARADAY SYMPOSIA OF THE CHEMICAL SOCIETY"
    },
    {
      "key": "e_1_2_1_34_1",
      "doi-asserted-by": "crossref",
      "first-page": "57",
      "DOI": "10.1016/0022-2836(73)90354-9",
      "volume": "74",
      "year": "1973",
      "unstructured": "PULSINELLI, P.D., STRUCTURE OF DEOXYHEMOGLOBIN YAKIMA - HIGH-AFFINITY MUTANT FORM EXHIBITING OXY-LIKE ALPHA1 BETA2 SUBUNIT INTERACTIONS, JOURNAL OF MOLECULAR BIOLOGY 74: 57 (1973).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_35_1",
      "doi-asserted-by": "crossref",
      "first-page": "31",
      "DOI": "10.1016/S0022-2836(83)80313-1",
      "volume": "171",
      "year": "1983",
      "unstructured": "SHAANAN, B, STRUCTURE OF HUMAN OXYHEMOGLOBIN AT 2.1 A RESOLUTION, JOURNAL OF MOLECULAR BIOLOGY 171: 31 (1983).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_36_1",
      "first-page": "1697",
      "volume": "82",
      "year": "1985",
      "unstructured": "SHIH, HHL, STRUCTURE OF PROTEINS WITH SINGLE-SITE MUTATIONS - A MINIMUM PERTURBATION APPROACH, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 82: 1697 (1985).",
      "journal-title": "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA"
    },
    {
      "key": "e_1_2_1_37_1",
      "doi-asserted-by": "crossref",
      "first-page": "281",
      "DOI": "10.1016/0097-8485(84)85020-2",
      "volume": "8",
      "year": "1984",
      "unstructured": "TEMBE, B.L., LIGAND RECEPTOR INTERACTIONS, COMPUTERS & CHEMISTRY 8: 281 (1984).",
      "journal-title": "COMPUTERS & CHEMISTRY"
    },
    {
      "key": "e_1_2_1_38_1",
      "doi-asserted-by": "crossref",
      "first-page": "177",
      "DOI": "10.1111/j.1365-2141.1977.tb00575.x",
      "volume": "35",
      "year": "1977",
      "unstructured": "WEATHERALL, D.J., HEMOGLOBIN RADCLIFFE (ALPHA-2 BETA-2 99(GI)ALA) - HIGH OXYGEN-AFFINITY VARIANT CAUSING FAMILIAL POLYCYTHEMIA, BRITISH JOURNAL OF HAEMATOLOGY 35: 177 (1977).",
      "journal-title": "BRITISH JOURNAL OF HAEMATOLOGY"
    },
    {
      "key": "e_1_2_1_39_1",
      "doi-asserted-by": "crossref",
      "first-page": "179",
      "DOI": "10.1016/S0022-2836(75)80108-2",
      "volume": "98",
      "year": "1975",
      "unstructured": "WISHNER, B.C., CRYSTAL-STRUCTURE OF SICKLE-CELL DEOXYHEMOGLOBIN AT 5 A RESOLUTION, JOURNAL OF MOLECULAR BIOLOGY 98: 179 (1975).",
      "journal-title": "JOURNAL OF MOLECULAR BIOLOGY"
    },
    {
      "key": "e_1_2_1_40_1",
      "doi-asserted-by": "crossref",
      "first-page": "2366",
      "DOI": "10.1063/1.455080",
      "volume": "89",
      "year": "1988",
      "unstructured": "YU, H.A., A THERMODYNAMIC ANALYSIS OF SOLVATION, JOURNAL OF CHEMICAL PHYSICS 89: 2366 (1988).",
      "journal-title": "JOURNAL OF CHEMICAL PHYSICS"
    },
    {
      "key": "e_1_2_1_41_1",
      "unstructured": "YU H unpublished data."
    }
  ],
  "container-title": "Science",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://www.science.org/doi/pdf/10.1126/science.2727695",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2024,
        1,
        13
      ]
    ],
    "date-time": "2024-01-13T04:27:50Z",
    "timestamp": 1705120070000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://www.science.org/doi/10.1126/science.2727695"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1989,
        6,
        2
      ]
    ]
  },
  "references-count": 41,
  "journal-issue": {
    "issue": "4908",
    "published-print": {
      "date-parts": [
        [
          1989,
          6,
          2
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1126/science.2727695"
  ],
  "URL": "http://dx.doi.org/10.1126/science.2727695",
  "relation": {},
  "ISSN": [
    "0036-8075",
    "1095-9203"
  ],
  "subject": [],
  "container-title-short": "Science",
  "published": {
    "date-parts": [
      [
        1989,
        6,
        2
      ]
    ]
  }
}