interaction network in DHFR. PLoS Comput
Biol 3(6):e117
4. Ma B, Nussinov R (2014) Druggable orthosteric and allosteric hot spots to target proteinprotein interactions. Curr Pharm Des 20
(8):1293–1301
5. Zhan C, Qi R, Wei G, Guven-Maiorov E,
Nussinov R, Ma B (2016) Conformational
dynamics of cancer-associated MyD88-TIR
domain mutant L252P (L265P) allosterically
tilts the landscape toward homo-dimerization.
Protein Eng Des Sel 29(9):347–354. https://
doi.org/10.1093/protein/gzw033
6. Ma B, Nussinov R (2016) Protein dynamics:
conformational footprints. Nat Chem Biol 12
(11):890–891.
https://doi.org/10.1038/
nchembio.2212
7. Keskin O (2007) Binding induced conformational changes of proteins correlate with their
intrinsic fluctuations: a case study of antibodies. BMC Struct Biol 7:31. https://doi.org/
10.1186/1472-6807-7-31
8. Thielges MC, Zimmermann Jr YW, Oda M,
Romesberg FE (2008) Exploring the energy
landscape of antibodyÀ antigen complexes:
protein dynamics, flexibility, and molecular recognition. Biochemistry 47(27):7237–7247
9. Li T, Tracka MB, Uddin S, Casas-Finet J,
Jacobs DJ, Livesay DR (2014) Redistribution
of flexibility in stabilizing antibody fragment
mutants follows Le Chatelier’s principle.
PLoS One 9(3):e92870. https://doi.org/10.
1371/journal.pone.0092870
10. Mian IS, Bradwell AR, Olson AJ (1991) Structure, function and properties of antibody binding sites. J Mol Biol 217(1):133–151
11. Torres M, Casadevall A (2008) The immunoglobulin constant region contributes to affinity
and specificity. Trends Immunol 29(2):91–97
12. Adachi M, Kurihara Y, Nojima H, TakedaShitaka M, Kamiya K, Umeyama H (2003)
Interaction between the antigen and antibody
is controlled by the constant domains: Normal
mode dynamics of the HEL–HyHEL-10 complex. Protein Sci 12(10):2125–2131
13. Pritsch O, Hudry-Clergeon G, Buckle M,
Pe ´tillot Y, Bouvet JP, Gagnon J, Dighiero G
(1996) Can immunoglobulin C (H) 1 constant
region domain modulate antigen binding affinity of antibodies? J Clin Investig 98(10):2235
14. Dam TK, Torres M, Brewer CF, Casadevall A
(2008) Isothermal titration calorimetry reveals
differential binding thermodynamics of variable region-identical antibodies differing in
constant region for a univalent ligand. J Biol
Chem 283(46):31366–31370
15. Tudor D, Yu H, Maupetit J, Drillet A-S,
Bouceba T, Schwartz-Cornil I, Lopalco L,
Tuffery P, Bomsel M (2012) Isotype modulates
epitope specificity, affinity, and antiviral activities of anti–HIV-1 human broadly neutralizing
2F5 antibody. Proc Natl Acad Sci 109
(31):12680–12685
16. Li T, Tracka MB, Uddin S, Casas-Finet J,
Jacobs DJ, Livesay DR (2015) Rigidity
emerges during antibody evolution in three
distinct antibody systems: evidence from
QSFR analysis of fab fragments. PLoS Comput
Biol 11(7):e1004327. https://doi.org/10.
1371/journal.pcbi.1004327
17. Pellequer JL, Chen SW, Roberts VA, Tainer JA,
Getzoff ED (1999) Unraveling the effect of
changes in conformation and compactness at
the antibody VL-VH interface upon antigen
binding. J Mol Recognit 12(4):267–275
18. Janda A, Casadevall A (2010) Circular Dichroism reveals evidence of coupling between
immunoglobulin constant and variable region
secondary structure. Mol Immunol 47
(7):1421–1425
19. Sela-Culang I, Kunik V, Ofran Y (2015) The
structural basis of antibody-antigen recognition. Immune system modeling and analysis.
Front Immunol. https://doi.org/10.3389/
fimmu.2013.00302
20. Oda M, Kozono H, Morii H, Azuma T (2003)
Evidence of allosteric conformational changes
in the antibody constant region upon antigen
binding. Int Immunol 15(3):417–426
21. Sela-Culang I, Alon S, Ofran Y (2012) A systematic comparison of free and bound antibodies reveals binding-related conformational
changes. J Immunol 189(10):4890–4899
22. Kanyo ZF, Pan K-M, Williamson RA, Burton
DR, Prusiner SB, Fletterick RJ, Cohen FE
(1999) Antibody binding defines a structure
for an epitope that participates in the PrP C!
PrP Sc conformational change. J Mol Biol 293
(4):855–863
23. Kale L, Skeel R, Bhandarkar M, Brunner R,
Gursoy A, Krawetz N, Phillips J, Shinozaki A,
Varadarajan K, Schulten K (1999) NAMD2:
greater scalability for parallel molecular dynamics. J Comput Phys 151(1):283–312
24. 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, WiorkiewiczKuczera J, Yin D, Karplus M (1998) All-atom
empirical potential for molecular modeling and
182
Jun Zhao et al.
Biol 3(6):e117
4. Ma B, Nussinov R (2014) Druggable orthosteric and allosteric hot spots to target proteinprotein interactions. Curr Pharm Des 20
(8):1293–1301
5. Zhan C, Qi R, Wei G, Guven-Maiorov E,
Nussinov R, Ma B (2016) Conformational
dynamics of cancer-associated MyD88-TIR
domain mutant L252P (L265P) allosterically
tilts the landscape toward homo-dimerization.
Protein Eng Des Sel 29(9):347–354. https://
doi.org/10.1093/protein/gzw033
6. Ma B, Nussinov R (2016) Protein dynamics:
conformational footprints. Nat Chem Biol 12
(11):890–891.
https://doi.org/10.1038/
nchembio.2212
7. Keskin O (2007) Binding induced conformational changes of proteins correlate with their
intrinsic fluctuations: a case study of antibodies. BMC Struct Biol 7:31. https://doi.org/
10.1186/1472-6807-7-31
8. Thielges MC, Zimmermann Jr YW, Oda M,
Romesberg FE (2008) Exploring the energy
landscape of antibodyÀ antigen complexes:
protein dynamics, flexibility, and molecular recognition. Biochemistry 47(27):7237–7247
9. Li T, Tracka MB, Uddin S, Casas-Finet J,
Jacobs DJ, Livesay DR (2014) Redistribution
of flexibility in stabilizing antibody fragment
mutants follows Le Chatelier’s principle.
PLoS One 9(3):e92870. https://doi.org/10.
1371/journal.pone.0092870
10. Mian IS, Bradwell AR, Olson AJ (1991) Structure, function and properties of antibody binding sites. J Mol Biol 217(1):133–151
11. Torres M, Casadevall A (2008) The immunoglobulin constant region contributes to affinity
and specificity. Trends Immunol 29(2):91–97
12. Adachi M, Kurihara Y, Nojima H, TakedaShitaka M, Kamiya K, Umeyama H (2003)
Interaction between the antigen and antibody
is controlled by the constant domains: Normal
mode dynamics of the HEL–HyHEL-10 complex. Protein Sci 12(10):2125–2131
13. Pritsch O, Hudry-Clergeon G, Buckle M,
Pe ´tillot Y, Bouvet JP, Gagnon J, Dighiero G
(1996) Can immunoglobulin C (H) 1 constant
region domain modulate antigen binding affinity of antibodies? J Clin Investig 98(10):2235
14. Dam TK, Torres M, Brewer CF, Casadevall A
(2008) Isothermal titration calorimetry reveals
differential binding thermodynamics of variable region-identical antibodies differing in
constant region for a univalent ligand. J Biol
Chem 283(46):31366–31370
15. Tudor D, Yu H, Maupetit J, Drillet A-S,
Bouceba T, Schwartz-Cornil I, Lopalco L,
Tuffery P, Bomsel M (2012) Isotype modulates
epitope specificity, affinity, and antiviral activities of anti–HIV-1 human broadly neutralizing
2F5 antibody. Proc Natl Acad Sci 109
(31):12680–12685
16. Li T, Tracka MB, Uddin S, Casas-Finet J,
Jacobs DJ, Livesay DR (2015) Rigidity
emerges during antibody evolution in three
distinct antibody systems: evidence from
QSFR analysis of fab fragments. PLoS Comput
Biol 11(7):e1004327. https://doi.org/10.
1371/journal.pcbi.1004327
17. Pellequer JL, Chen SW, Roberts VA, Tainer JA,
Getzoff ED (1999) Unraveling the effect of
changes in conformation and compactness at
the antibody VL-VH interface upon antigen
binding. J Mol Recognit 12(4):267–275
18. Janda A, Casadevall A (2010) Circular Dichroism reveals evidence of coupling between
immunoglobulin constant and variable region
secondary structure. Mol Immunol 47
(7):1421–1425
19. Sela-Culang I, Kunik V, Ofran Y (2015) The
structural basis of antibody-antigen recognition. Immune system modeling and analysis.
Front Immunol. https://doi.org/10.3389/
fimmu.2013.00302
20. Oda M, Kozono H, Morii H, Azuma T (2003)
Evidence of allosteric conformational changes
in the antibody constant region upon antigen
binding. Int Immunol 15(3):417–426
21. Sela-Culang I, Alon S, Ofran Y (2012) A systematic comparison of free and bound antibodies reveals binding-related conformational
changes. J Immunol 189(10):4890–4899
22. Kanyo ZF, Pan K-M, Williamson RA, Burton
DR, Prusiner SB, Fletterick RJ, Cohen FE
(1999) Antibody binding defines a structure
for an epitope that participates in the PrP C!
PrP Sc conformational change. J Mol Biol 293
(4):855–863
23. Kale L, Skeel R, Bhandarkar M, Brunner R,
Gursoy A, Krawetz N, Phillips J, Shinozaki A,
Varadarajan K, Schulten K (1999) NAMD2:
greater scalability for parallel molecular dynamics. J Comput Phys 151(1):283–312
24. 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, WiorkiewiczKuczera J, Yin D, Karplus M (1998) All-atom
empirical potential for molecular modeling and
182
Jun Zhao et al.