Python Tools for Computational Molecular Biology
Python Tools for Computational Molecular Biology
Mikael Trellet mikael.trellet@gmail.com
Mentors
João Rodrigues
Eric Talevich
You can find a descriptive and a “how to use” part of the Interface analysis module at the following link:
Analysis of protein-protein complexes interfaces at a residue level yields significant information on the overall binding process. Such information can be broadly used for example in binding affinity studies, interface design, and enzymology. To tap into it, there is a need for tools that systematically and automatically analyze protein structures, or that provide means to this end. Protorop (http://www.bioinformatics.sussex.ac.uk/protorp/) is an example of such a tool and the elevated number of citations the server has had since its publication acknowledge its importance. However, being a webserver, Protorop is not suited for large-scale analysis and it leaves the community dependent on its maintainers to keep the service available. On the other hand, Biopython’s structural biology module, Bio.PDB, provides the ideal parsing machinery and programmatic structures for the development of an offline, open-source library for interface analysis. Such a library could be easily used in large-scale analysis of protein-protein interfaces, for example in the CAPRI experiment evaluation or in benchmark statistics. It would be also reasonable, if time permits, to extend this module to deal with protein-DNA or protein-RNA complexes, as Biopython supports nucleic acids already.
Unit tests will be perfomed along the project, allowing to do only a larger test at the end gathering every tests already performed.
Then the aim will be to optimized, if possible, some parts of the code in efficiency and rapidity without changes at algorithmic level. Several days will be booked to package code and be sure that everything can communicate with Biopython.
We began to think of an easy way to add the Interface as a new part of the SMCRA scheme. The idea was to have this new scheme = SM-I-CRA. Unfortunately the Interface object is not as well defined as just a child of model and a parent of chains. Indeed, the main part of the interface is residues, and even residues pairs. We want to keep the information of the chain but we can’t keep them as they are defined actually, since we will get some overlaps, duplication and miscompatibility between the chains of our model and the chains of our interface. In the same way, our try to link the creation of the interface with existing modules as StructureBuilder and Model wasn’t successful. So, we decided to simplify a bit the concept in adding the classes related to the Interface in an independent way. Obviously links will exist between the different levels of SMCRA but Interface would be considered now as a parallel entity, not integrated completely in the SMCRA scheme.
Interface.py is the definition of the Interface object inherited from Entity with the following methods : __init__(self, id), add(self, entity) and get_chains(self).
The add module overrides the add method of Entity in order to have an easy way to class residues according to their respective chains. The get_chains modules returns the chains involved in the interface defined by the Interface object.
The second class created is InterfaceBuilder.py which deals directly with the interface building (hard to guess..!) We find these different modules : __init__(self, model, id=None, threshold=5.0, include_waters=False, *chains), _unpack_chains(self, list_of_tuples), get_interface(self), _add_residue(self, residue), _build_interface(self, model, id, threshold, include_waters=False, *chains)
__init__ : In order to initialize an interface you need to provide the model for which you want to calculate the interface, that’s the only mandatory argument.
_unpack_chains: Method used by __init__ so as to create self.chain_list, variable read in many parts of the class. It transforms a list of tuples (given by the user) in a list of characters representing the chains which will be involved in the definition of the interface.
get_interface: Returns simply the interface
_add_residue: Allows the user to add some specific residues to his interface
_build_interface: The machinery to build the interface, it uses NeighborSearch and Selection in order to define the interface depending on the arguments given by the user.
Interface.py InterfaceBuilder.py
In order to have several useful information about residues and in the aim to use them for further calculations inside interfaces, we want to implement a subclass of residues. This new class would be integrate as an inherited class of Residues (as DisorderedResidues) and would calculate by default few information about residues as polar charge, hydrophobicity or weight. We first thought to create a copy of an existing residue to create an extended residue but, with regards to the memory consumming, we preferred change directly the residue type. Thus, we change the class of the residue and perform calculation during the initialization of the new ExtendedResidue class. So, changing of a residue is done by Residue.extend()
ExtendedResidue is an inherited class from Residue, these are the different methods inside :
__init__: Sets charge, mass and hydrophobicity of a residue.
__repr__: Defines a new id for the residue, based on the residue id.
set_hydrophobicity: Sets the residue hydrophobicoty depending on the scale choice, KD {Kyle and Doolittle}, OHM {Sweet and Eisenberg} or consensus (by default= consensus). Returns the scale chosen.
set_charge: Sets the relative charge of a residue with regards to its pka and the pH defined by the user (by default 7.0)
set_mass: Sets the mass of a residue according to its atoms mass
In order to work with complexes interface, few important information are needed. Some of them are calculated during the initialization of the interface and others are calculated via functions.
Private functions in InterfaceBuilder (used during the Interface initialization):
_secondary_structure: Calculates secondary structure of each residue of the Interface using DSSP.
_rsa_calculation: Used to define the interface according to the residues accessibility.
Public functions in Interface (used by the user):
set_neighbors:Creates a dictionary of neighbors for each residue of the interface.
calculate_accessibility:Calculates the buried surface area of the complex and indirectly the accessibility of the interface. Total accessibility and accessibility of the chains are also calculated in this function. This calculation is done via the NACCESS module.
Several ways are used by scientists to measure differences between two complexes. In particular in structural biology, an important part of the work is the analyse of the models generated by a scientific method. Reliability and accurately of a docking for instance. To know if a model can be considered as acceptable, a reference is taken and from this reference, some calculations are done, comparing models with reference. We can cite RMSD or Fraction of native contacts for example. These are two calculations we added in the Interface analysis module.
interface_ref.rmsd(interface_model): This function used Superimposer module in order to calculate Root Mean Square Deviation between residues of 2 interfaces. It gives the interface RMSD as well.
interface_ref.fnat(interface_model): This function calculates the fraction of common contacts between 2 interfaces.