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BindProfX logo

BindProfX is a program to predict protein-protein binding affinity change upon mutation of residues at interface. When given a complex structure, it will extract the protein-protein interaction interface structure and use iAlign to search the interface against protein complex structure database to find homologous interfaces. A pair of sequence profiles will be constructured from the interface structure alignment. From the sequence profile, a conservation score ΔΔGcons will be calculated. For singe point mutation, the profile conservation score can be optionally combined with FoldX physics potential ΔΔGfoldx to predict the binding affinity change.

BindProfX flowchart
Figure 1: The BindProfX pipeline to predict binding affinity change upon interface mutation by combining interface sequence profile and FoldX physics force field.

BindProfX: Input Format.
Mutation format: BindProfX accepts mutations in FoldX format, which include 'WT_residue', 'Chain_ID', 'residue_number', 'mutant_residue', example:
    QA22D;
    HA18F,QA22D;
Note:
  • One mutation set per line and each line ends in semicolon.
  • If one mutation set has more than one mutation, separate them by commas.
  • In the above example, the first line represents a single mutation on Chain A where Glu22 is mutated to Asp. The second line represents a double mutations on Chain A where His18 is mutated to Phe and Glu22 is mutated to Asp.



BindProfX: Understanding the output.
Binding Affinity Change Upon Mutations: (Short Answer) Mutations that stablize protein complex have more negative ΔΔG.
(Long Answer) The binding affinity between two proteins is measured by Gibbs free energy change ΔG=G(complex)-G(monomers) when two monomers form a complex. The more negative ΔG is, the more stable is the complex. The effect of mutation on binding affinity is measured by different of free energy change between mutant and wild type: ΔΔGwt→mut =ΔGmut-ΔGwt. A strongly favarable mutations has ΔΔG ≤ -1 kcal⁄mol.

Interface Alignment: When BindProfX predicts ΔΔG of interface residue mutations, it uses iAlign to align the Protein-Protein Interaction (PPI) interface structure of target protein to a set of PPI interface structures from PIFACE database. From the interface alignment, a pair of interface sequence profile is constructured. From this profile, the profile conservation score is calculated.


BindProfX: Advanced Options.
Interface similarity cutoff: By default BindProfX will only look for highly similar interface (IS-score>0.55) among known protein complex structures. IS-score should be in [0,1], with a higher value indicating a closer interface structure similarity. IS-score cutoff of 0.55 gives the best prediction.

Score to use: When calculating binding affinity change upon singe point mutation, BindProfX can either only uses profile conservation score derived from interface structure alignment (Interface profile only), or combines conservation score and FoldX physics-based energy (Interface profile and physics potential). Default is interface profile only. For high-resolution crystal structures, We find that combining interface profile and physics potential provides slightly better prediction than using interface conservation score alone.


Reference:

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