A physical model for PDZ-domain/peptide interactions.
The PDZ domain is an interaction motif that recognizes and binds the C-terminal peptides of target proteins. PDZ domains are ubiquitous in nature and help assemble multiprotein complexes that control cellular organization and signaling cascades. We present an optimized energy function to predict the binding free energy (ΔΔG) of PDZ domain/peptide interactions computationally. Geometry-optimized models of PDZ domain/peptide interfaces were built using ROSETTA: , and protein and peptide side chain and backbone degrees of freedom are minimized simultaneously. Using leave-one-out cross-validation, ROSETTA: 's energy function is adjusted to reproduce experimentally determined ΔΔG values with a correlation coefficient of 0.66 and a standard deviation of 0.79 kcal mol(-1). The energy function places an increased weight on hydrogen bonding interactions when compared to a previously developed method to analyze protein/protein interactions. Binding free enthalpies (ΔΔH) and entropies (ΔS) are predicted with reduced accuracies of R = 0.60 and R = 0.17, respectively. The computational method improves prediction of PDZ domain specificity from sequence and allows design of novel PDZ domain/peptide interactions.
Kaufmann
Kristian
K
Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
Shen
Nicole
N
Mizoue
Laura
L
Meiler
Jens
J
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D019277:Entropy; D006860:Hydrogen Bonding; D008958:Models, Molecular; D054731:PDZ Domains; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D010455:Peptides
Structure. 2003 Jul;11(7):845-53
12842047
Nat Biotechnol. 1997 Apr;15(4):336-42
9094134
PLoS Biol. 2008 Sep 30;6(9):e239
18828675
J Neurosci. 1999 Sep 15;19(18):7770-80
10479680
Science. 1997 Dec 19;278(5346):2075-80
9405336
Nat Struct Mol Biol. 2004 Apr;11(4):371-9
15034550
Biochemistry. 2006 May 2;45(17):5567-75
16634638
Nat Rev Neurosci. 2004 Oct;5(10):771-81
15378037
J Biol Chem. 2002 Feb 22;277(8):5699-702
11741967
Sci STKE. 2004 Feb 03;2004(219):pl2
14872095
Cell. 1996 Jun 28;85(7):1067-76
8674113
Protein Sci. 1997 Feb;6(2):464-8
9041651
Science. 2007 Jul 20;317(5836):364-9
17641200
Mol Cell. 2002 Oct;10(4):895-905
12419232
J Mol Biol. 2008 Feb 1;375(5):1457-68
18155042
J Mol Biol. 2003 Aug 1;331(1):281-99
12875852
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14116-21
12381794
Mol Cell. 2004 Mar 12;13(5):665-76
15023337
J Mol Biol. 2003 Feb 28;326(4):1239-59
12589766
Structure. 2003 Apr;11(4):459-68
12679023
Biochemistry. 2006 Mar 21;45(11):3674-83
16533050
FEBS J. 2006 Nov;273(22):5219-29
17069616
Science. 2005 Sep 16;309(5742):1868-71
16166519
Nucleic Acids Res. 2000 Jan 1;28(1):231-4
10592234
Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W235-8
16845000
J Mol Biol. 2006 Mar 31;357(3):917-27
16473368
Proteins. 1999 May 1;35(2):133-52
10223287
Nat Rev Drug Discov. 2004 Dec;3(12):1047-56
15573103
J Biol Chem. 2003 Mar 7;278(10):8501-7
12493751
Sci STKE. 2003 Apr 22;2003(179):RE7
12709532
Biochemistry. 2007 May 29;46(21):6340-52
17474715
J Virol. 2007 Apr;81(7):3618-26
17267502
J Mol Biol. 1993 Mar 20;230(2):543-74
8464064
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10383-8
10984534
Nat Biotechnol. 2008 Sep;26(9):1041-5
18711339