# Copyright Yair Benita Y.Benita@pharm.uu.nl
# Biopython (http://biopython.org) license applies

"""Calculate isoelectric points of polypeptides using methods of Bjellqvist.

pK values and the methos are taken from::

    * Bjellqvist, B.,Hughes, G.J., Pasquali, Ch., Paquet, N., Ravier, F., Sanchez,
    J.-Ch., Frutiger, S. & Hochstrasser, D.F.
    The focusing positions of polypeptides in immobilized pH gradients can be predicted
    from their amino acid sequences. Electrophoresis 1993, 14, 1023-1031.

    * Bjellqvist, B., Basse, B., Olsen, E. and Celis, J.E.
    Reference points for comparisons of two-dimensional maps of proteins from
    different human cell types defined in a pH scale where isoelectric points correlate
    with polypeptide compositions. Electrophoresis 1994, 15, 529-539.

I designed the algorithm according to a note by David L. Tabb, available at:
http://fields.scripps.edu/DTASelect/20010710-pI-Algorithm.pdf

"""

__docformat__ = "restructuredtext en"

positive_pKs = {'Nterm': 7.5, 'K': 10.0, 'R': 12.0, 'H': 5.98}
negative_pKs = {'Cterm': 3.55, 'D': 4.05, 'E': 4.45, 'C': 9.0, 'Y': 10.0}
pKcterminal = {'D': 4.55, 'E': 4.75}
pKnterminal = {'A': 7.59, 'M': 7.0, 'S': 6.93, 'P': 8.36, 'T': 6.82, 'V': 7.44, 'E': 7.7}
charged_aas = ('K', 'R', 'H', 'D', 'E', 'C', 'Y')


# access this module through ProtParam.ProteinAnalysis class.
# first make a ProteinAnalysis object and then call its isoelectric_point method.
class IsoelectricPoint(object):
    def __init__(self, ProteinSequence, AminoAcidsContent):
        self.sequence = ProteinSequence
        self.charged_aas_content = self._select_charged(AminoAcidsContent)

    # This function creates a dictionary with the contents of each charged aa,
    # plus Cterm and Nterm.
    def _select_charged(self, AminoAcidsContent):
        charged = {}
        for aa in charged_aas:
            charged[aa] = float(AminoAcidsContent[aa])
        charged['Nterm'] = 1.0
        charged['Cterm'] = 1.0
        return charged

    # This function calculates the total charge of the protein at a given pH.
    def _chargeR(self, pH, pos_pKs, neg_pKs):
        PositiveCharge = 0.0
        for aa, pK in pos_pKs.items():
            CR = 10 ** (pK - pH)
            partial_charge = CR / (CR + 1.0)
            PositiveCharge += self.charged_aas_content[aa] * partial_charge

        NegativeCharge = 0.0
        for aa, pK in neg_pKs.items():
            CR = 10 ** (pH - pK)
            partial_charge = CR / (CR + 1.0)
            NegativeCharge += self.charged_aas_content[aa] * partial_charge

        return PositiveCharge - NegativeCharge

    # This is the action function, it tries different pH until the charge of the protein is 0 (or close).
    def pi(self):
        pos_pKs = dict(positive_pKs)
        neg_pKs = dict(negative_pKs)
        nterm = self.sequence[0]
        cterm = self.sequence[-1]
        if nterm in pKnterminal:
            pos_pKs['Nterm'] = pKnterminal[nterm]
        if cterm in pKcterminal:
            neg_pKs['Cterm'] = pKcterminal[cterm]

        # Bracket between pH1 and pH2
        pH = 7.0
        Charge = self._chargeR(pH, pos_pKs, neg_pKs)
        if Charge > 0.0:
            pH1 = pH
            Charge1 = Charge
            while Charge1 > 0.0:
                pH = pH1 + 1.0
                Charge = self._chargeR(pH, pos_pKs, neg_pKs)
                if Charge > 0.0:
                    pH1 = pH
                    Charge1 = Charge
                else:
                    pH2 = pH
                    Charge2 = Charge
                    break
        else:
            pH2 = pH
            Charge2 = Charge
            while Charge2 < 0.0:
                pH = pH2 - 1.0
                Charge = self._chargeR(pH, pos_pKs, neg_pKs)
                if Charge < 0.0:
                    pH2 = pH
                    Charge2 = Charge
                else:
                    pH1 = pH
                    Charge1 = Charge
                    break

        # Bisection
        while pH2 - pH1 > 0.0001 and Charge != 0.0:
            pH = (pH1 + pH2) / 2.0
            Charge = self._chargeR(pH, pos_pKs, neg_pKs)
            if Charge > 0.0:
                pH1 = pH
                Charge1 = Charge
            else:
                pH2 = pH
                Charge2 = Charge

        return pH
