Microscale Electrostatics in Mitosis, Journal of Electrostatics, vol. 54, 210-232 (2002).
Comments on biophysics research
In spite of a series of ingenious experiments over the last 30 years,
the causes for most of the mitotic
motions remains unclear.
The current paradigm in molecular biology requires that specific
molecular geometries, for force generation be identified. However, it
is possible to account for mitotic motions in terms of
experimentally known cellular electric charge distributions
on molecules interacting over nanometer distances.
This is the approach that I have
taken in the series of papers listed here.
The known charge in mitotic chromosome motions resides at kinetochores, centrosomes, and on chromosome arms. In 2002 and 2005 Physical Review E and Journal of Electrostatics papers (see above), I argued that indirect experimental evidence indicates that pole-facing "plates" of kinetochores manifest positive charge that interacts with negative charge at and near the plus ends of microtubules to generate force for poleward chromosome movements. Subsequently, experiments have implicated positively charged molecules in kinetochores in establishing a dynamic coupling to microtubules for force generation during mitosis [Miller SA et al., Curr. Biol. 2008;18:1785].
Assuming positive charge at kinetochores, and negative charge at and near the free plus ends of microtubules, it is possible to derive the magnitude of the maximum (tension) force per microtubule for poleward chromosome motions that falls within the experimental range [Gagliardi LJ and Shain DH, Cell Division 2016; 11:14].
In the above-mentioned 2002 and 2005 Physical Review E and Journal of Electrostatics papers I also proposed that indirect experimental evidence is consistent with negative charge on centrosomes. Experimental measurements have confirmed this [Hormeno S. et al., Biophys. J. 2009; 97:1022]. Experimental verification of net negative charge on centrosomes implies that expression of positive charge on free minus microtubule ends will be favored. This is supported by large scale computer calculations on microtubules [Baker NA et al., Proc. Natl. Acad. Sci. 2001; 98:10037]. The interaction of this charge with a negatively charged centrosome may be responsible for polar poleward force generation. A calculation of the polar poleward electrostatic force per microtubule that falls within the experimental range has been carried out [Gagliardi LJ and Shain DH, Cell Division 2014; 9:5].
As mentioned above, models within the molecular biology paradigm are being sought (or advanced) to explain recent experiments suggesting that highly basic kinetochore molecules interact with negative charge on microtubules to couple kinetochores to microtubules. As in the situation involving models that center partially or wholly on simulations, these approaches are quite complex in their assumptions and primarily attempt to address one or two mitotic motions, most notably poleward force generation at kinetochores. Critical experimental observations such as the "slip-clutch" mechanism [Maiato H et al., J. Cell Science 2004; 117:5461], observations of calcium ion concentration on anaphase-A chromosome motion [Zhang DH, Callaham DA, Hepler PK, J. Cell Biol. 1990; 111:171], and polar generation of force for poleward chromosome motions are not addressed. In the model that I have proposed, interactions between stably bound molecular charge distributions can account for these, as well as poleward force generation at kinetochores.
Regarding molecular motor contributions to mitotic motions, it is generally thought that molecular motors are likely involved in the sliding microtubule sidewall "capture" motion of chromatid pairs. The case for molecular motors as the cause for post-attachment chromosome motions is considerably less convincing.
Identifying the motive force is central to explaining post-attachment chromosome motions during mitosis. Presently, there is no consensus on what it is. I have proposed a minimal assumptions model for post-attachment chromosome movements based on the dynamic instability of microtubules and nanoscale electrostatics. Given the electrical properties of (tubulin and) microtubules, and charge distributions on kinetochores, centrosomes and chromosome arms, as well as the pH-dependent dynamics of microtubules, it is possible to account for post-attachment prometaphase, metaphase, and anaphase-A chromosome motions within a comprehensive model.