Computational Biophysics alexov by Ns92M02

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									Computational Biophysics and Bioinformatics lab




 Predicting protein-protein interactions and the corresponding 3D
structures of protein-protein complexes by homology. Using the 3D
         structures to compute biophysical characteristics




                            Emil Alexov
                http://www.ces.clemson.edu/compbio
From Genes  Proteins  Protein-protein complexes
Modeling biophysical characteristics of protein-protein interactions


      Part A. Salt dependence of protein-protein binding




         AB                          A                      B

        mobile ions – red – negative charge, blue – positive charge

       Two questions to be addressed:
       (a) Linear vs non-linear Poisson-Boltzmann equation

        . (r ) (r )  4 (r )   (r ) 2 (r ) sinh( / kT )
       (b) Possible correlations in respect to macroscopic characteristics
        net charge, interfacial area, charge at the interface etc…
                                        Part A. Salt dependence of protein-protein binding
                                                                                                                                                                                                                  -               -
                                         hetero                                                     homo                                                                                     Gel ( I )  Gsalt ( AB )  Gsalt ( A)  Gsalt ( B)
                   20                                                              120
                                                                 A                                                                                                 B

                                                                                                                                                                                                                                    ●
                                                                                   100
                   15
                                                                                   80
                                                                                                                                                                                                                       ●




                                                                           Count
       Count




                   10                                                              60
                                                                                                                                                                                                               ●
                                                                                   40                                                                                                                      ●           slope
                    5
                                                                                   20
                                                                                                                                                                                                                      ln(I)
                    0                                                               0
                           -2    -1     0 1 2 3 4 5              6                       -8   -6    -4   -2   0       2                                        4
                                      average Gel(I)/ln(I)                                  average Gel(I)/ln(I)




                                                                                                    G (I)/ln(I) (NLPB) - G (I)/ln(I) (LPB)
                         y = 0.9104 - 0.058079x R= 0.23119
                        y = 0.29261 - 0.099907x R= 0.31213                                                                                           6
                   8
                                                                                                                                                     5
                                                            NLPB
                   6
                                                            LPB                                                                                      4
                                                                                                                                         el
                   4
Gel(I)/ln(I)




                                                                                                                                                     3
                   2
                                                                                                                                                     2
                   0
                                                                                                                                                     1
                   -2
                                                                                                                                                     0
                   -4
                                                                                                                                                     -1
                   -6
                                                                                                                                         el




                     -15        -10      -5    0       5   10    15   20                                                                             -2
                                                                                                                                                      -15   -10       -5   0       5   10       15        20
                                                                                                                                                                                
                    Part B. Parameter dependence of protein-protein binding
                             Protein dielectric constant dependence
                          charmm27                                                  charmm27
             50                                                        50
                                   (in)=1                                                   (in)=1
                                   (in)=2                             40                    (in)=2
             40
                                   (in)=4                                                   (in)=4
                                   (in)=8                                                   (in)=8




                                                      percentage
percentage




             30                    (in)=20                            30                    (in)=20
                                                                                                                Hetero
             20                                                        20

             10                                                        10

             0                                                         0
              -50    0     50    100      150   200                     -50    0     50    100      150   200
                         G [kcal/mol]                                            G [kcal/mol]
                             el
                                                                                       el


                          charmm27                                                   charmm27
             50                                                        60
                                    (in)=1                                                  (in)=1
             40                     (in)=2                            50                    (in)=2
                                    (in)=4                                                  (in)=4
                                    (in)=8                            40                    (in)=8
percentage




                                                          percentage




             30                     (in)=20                                                 (in)=20           Homo
                                                                       30
             20
                                                                       20
             10
                                                                       10

             0                                                          0
              -50    0     50    100      150   200                      -50   0     50    100      150   200
                         G [kcal/mol]                                            G [kcal/mol]
                             el
                                             Part B. Parameter dependence of protein-protein binding
                                                             Force field dependence

                                  300                                                                       300
                                            y = -4.1241 + 0.95802x R= 0.9485                                       y = -8.6916 + 0.88949x R= 0.91945
        G [kcal/mol] Charmm




                                                                                     G [kcal/mol] OPLS
                                  200                                                                       200


                                  100                                                                       100


                                    0                                                                         0




                                                                                                       el
                            el




                                  -100                                                                      -100


                                  -200                                                                      -200
                                     -200      -100    0      100    200       300                             -200   -100    0      100    200        300
                                                                                                                         G [kcal/mol] Amber
                                                  G [kcal/mol] Amber                                                       el
                                                         el




                                 300
                                         y = -4.1986 + 0.90903x R= 0.94975
G [kcal/mol] OPLS




                                 200


                                 100                                                                          Conclusions:
                                                                                                              (a) Very good correlations
                                   0                                                                          (b) Quite many outliers
                   el




                                 -100


                                 -200
                                    -200      -100    0      100    200        300
                                                G [kcal/mol] Charmm
                                                    el
                            Acknowledgements
 Kemper Talley, Undergraduate student, Department of Physics and Astronomy
 Petras Kundrotas – Senior Scientist, Center for Bioinformatics, Kansas Univ.
 Radhey Shyam – PhD student, Department of Physics and Astronomy
 Shaolei Teng – PhD student, Department of Biochemistry and Genetics
 Rooplekha Mitra – PhD student, Department of Physics and Astronomy

 Indranil Mitra – PhD student, Department of Mathematical Sciences




The minimization of the structures used in this work was made possible by a Condor
pool deployed and maintained by Clemson Computing and Information Technology.
The authors would like to acknowledge the support of the staff from the Cyber
Infrastructure Technology Integration group, especially Barr Von Oehsen.

We thank Barr Von Oehsen and Matt Salzmann for the help with Axiom cluster

We thank Murray Daw for the help with Augustine cluster

This research was supported by an award to Clemson University from
the Howard Hughes Medical Institute Undergraduate Science Education Program.

We thank Eureka program.

								
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