ppRate

Computing protein-protein association rates

A service of the Baker Lab, Department of Biochemistry, University of Washington

Calculate association rates

Welcome to the ppRate server!

This application allows to compute association rates for protein-protein complexes from angular tolerances of mutual orientation.

To start a computation, enter the required values in the fields on the left and click Submit. When the computation is finished, the resulting association rate will be sent to you via email.
For a quick overview, a short getting-started guide is provided below.
For more details, please refer to the references listed on the right.
You can also view and download a copy of the C source code of the program (for personal use only). To compile it, you will need the GSL library.

Questions, suggestions?

Please feel free to contact us at maxl@u.washington.edu (M. Schlosshauer) with any questions or suggestions.

Getting started

Our model

The idea of our approach is to model protein-protein binding kinetics via the free diffusion of two spherical molecules with anisotropic reactivity. This diffusional problem can be solved exactly (see reference 1; download PDF).The reaction condition is formulated by specifying the ranges of mutual orientations of the two molecules for which complex formation will occur. We therefore do not require an exact mutual alignment of the binding partners, but instead assume that favorable short-range interactions "guide'" the molecules into their final bound configurations once the molecules are oriented within specified angular tolerances (see Fig. 1). These tolerances can therefore be viewed as an implicit modelling of attractive short-range forces. As our model completely neglects long-range forces (e.g., "electrostatic steering"), it can be used to give an estimate for the basal association rate.

Fig. 1: The relevant angles to describe the mutual orientation of the two spherical molecules.

How to obtain the angular tolerances

Estimates for the angular tolerances can be derived from free energy landscapes obtained by sampling configurations within and surrounding the native binding funnel. The method described in reference 1 (download PDF) consists of the following main steps (see also Fig. 2):

generate 1,000 alternative structures from the PDB structure of the native complex;
evaluate the interaction energy (energy landscapes) of each perturbed structure;
since the goal is to model diffusion in such energy landscapes as free diffusion with an effective capture region, define a capture energy cutoff E_c below which the partners are committed to bind as the average of the energies of the five lowest lying structures greater than 10 Å rmsd from the native complex;
among the structures with E < E_c, select the 10 structures with the largest values of θ_A+θ_B;
compute the angular constraints θ_A, θ_B, δφ, δχ from averaging over the values found in these structures.

Fig. 2: Free energy funnels around the native structure. The energy E and the angular deviation θ_Ais shown for a set of randomly perturbed structures of a protein--protein complex. The two parallel lines represent two different energy cutoffs, while the vertical lines indicate the resulting angular constraints.

Questions, suggestions?

Please feel free to contact us at maxl@u.washington.edu (M. Schlosshauer) with any questions or suggestions.

Credits

This service is the result of a collaboration between the Department of Physics (M. Schlosshauer) and Department of Biochemistry (D. Baker) at the University of Washington. Website developed and maintained by M. Schlosshauer. Webserver hosted by the Baker Lab, Department of Biochemistry, University of Washington.

References

1. Enter the radii of the two proteins:

R_A (Å): R_B (Å):

2. Enter the angular tolerances of mutual orientation for the two proteins:

θ_A (degs): θ_B (degs):

δφ (degs): δχ (degs):

3. Choose the level of precision for the calculation:

lower (faster computation, >30 minutes)
higher (longer computation, >90 minutes)

4. Enter your email address to which the result of the computation should be sent:

Email address:

Note: Computation times vary greatly depending on the server load. A single request to the server, with no other requests currently being processed, requires about 30/90 minutes (lower/higher precision). For multiple request being processed in parallel, CPU ressources will be shared among these requests and computation time will be accordingly longer.

M. Schlosshauer and D. Baker (2004). [download PDF]
Realistic protein-protein association rates from a simple diffusional model neglecting long-range interactions, free energy barriers, and landscape ruggedness.
Protein Science (13), 1660-1669.
M. Schlosshauer and D. Baker (2002). [download PDF]
A general expression for bimolecular association rates with orientational constraints.
Journal of Physical Chemistry B 106(46), 12079-12083.

ppRate Computing protein-protein association rates A service of the Baker Lab, Department of Biochemistry, University of Washington

Calculate association rates	Welcome to the ppRate server! This application allows to compute association rates for protein-protein complexes from angular tolerances of mutual orientation. To start a computation, enter the required values in the fields on the left and click Submit. When the computation is finished, the resulting association rate will be sent to you via email. For a quick overview, a short getting-started guide is provided below. For more details, please refer to the references listed on the right. You can also view and download a copy of the C source code of the program (for personal use only). To compile it, you will need the GSL library. Questions, suggestions? Please feel free to contact us at maxl@u.washington.edu (M. Schlosshauer) with any questions or suggestions. Getting started Our model The idea of our approach is to model protein-protein binding kinetics via the free diffusion of two spherical molecules with anisotropic reactivity. This diffusional problem can be solved exactly (see reference 1; download PDF).The reaction condition is formulated by specifying the ranges of mutual orientations of the two molecules for which complex formation will occur. We therefore do not require an exact mutual alignment of the binding partners, but instead assume that favorable short-range interactions "guide'" the molecules into their final bound configurations once the molecules are oriented within specified angular tolerances (see Fig. 1). These tolerances can therefore be viewed as an implicit modelling of attractive short-range forces. As our model completely neglects long-range forces (e.g., "electrostatic steering"), it can be used to give an estimate for the basal association rate. Fig. 1: The relevant angles to describe the mutual orientation of the two spherical molecules. How to obtain the angular tolerances Estimates for the angular tolerances can be derived from free energy landscapes obtained by sampling configurations within and surrounding the native binding funnel. The method described in reference 1 (download PDF) consists of the following main steps (see also Fig. 2): generate 1,000 alternative structures from the PDB structure of the native complex; evaluate the interaction energy (energy landscapes) of each perturbed structure; since the goal is to model diffusion in such energy landscapes as free diffusion with an effective capture region, define a capture energy cutoff E_c below which the partners are committed to bind as the average of the energies of the five lowest lying structures greater than 10 Å rmsd from the native complex; among the structures with E < E_c, select the 10 structures with the largest values of θ_A+θ_B; compute the angular constraints θ_A, θ_B, δφ, δχ from averaging over the values found in these structures. Fig. 2: Free energy funnels around the native structure. The energy E and the angular deviation θ_Ais shown for a set of randomly perturbed structures of a protein--protein complex. The two parallel lines represent two different energy cutoffs, while the vertical lines indicate the resulting angular constraints. Questions, suggestions? Please feel free to contact us at maxl@u.washington.edu (M. Schlosshauer) with any questions or suggestions. Credits This service is the result of a collaboration between the Department of Physics (M. Schlosshauer) and Department of Biochemistry (D. Baker) at the University of Washington. Website developed and maintained by M. Schlosshauer. Webserver hosted by the Baker Lab, Department of Biochemistry, University of Washington.	References
1. Enter the radii of the two proteins: R_A (Å): R_B (Å): 2. Enter the angular tolerances of mutual orientation for the two proteins: θ_A (degs): θ_B (degs): δφ (degs): δχ (degs): 3. Choose the level of precision for the calculation: lower (faster computation, >30 minutes) higher (longer computation, >90 minutes) 4. Enter your email address to which the result of the computation should be sent: Email address: Note: Computation times vary greatly depending on the server load. A single request to the server, with no other requests currently being processed, requires about 30/90 minutes (lower/higher precision). For multiple request being processed in parallel, CPU ressources will be shared among these requests and computation time will be accordingly longer.		M. Schlosshauer and D. Baker (2004). [download PDF] Realistic protein-protein association rates from a simple diffusional model neglecting long-range interactions, free energy barriers, and landscape ruggedness. Protein Science (13), 1660-1669. M. Schlosshauer and D. Baker (2002). [download PDF] A general expression for bimolecular association rates with orientational constraints. Journal of Physical Chemistry B 106(46), 12079-12083.
Copyright © 2004 Baker Lab, Department of Biochemistry, University of Washington. All rights reserved. Website last modified on 7/21/2004.