Mingang Li | Searcharxiv

arXiv2017

Single Molecule Studies Under Constant Force Using Model Based Robust Control Design

Optical tweezers have enabled important insights into intracellular transport through the investigation of motor proteins, with their ability to manipulate particles at the microscale, affording femto Newton force resolution. Its use to realize a constant force clamp has enabled vital insights into the behavior of motor proteins under different load conditions. However, the varying nature of disturbances and the effect of thermal noise pose key challenges to force regulation. Furthermore, often the main aim of many studies is to determine the motion of the motor and the statistics related to the motion, which can be at odds with the force regulation objective. In this article, we propose a mixed objective H2-Hinfinity optimization framework using a model-based design, that achieves the dual goals of force regulation and real time motion estimation with quantifiable guarantees. Here, we minimize the Hinfinity norm for the force regulation and error in step estimation while maintaining the H2 norm of the noise on step estimate within user specified bounds. We demonstrate the efficacy of the framework through extensive simulations and an experimental implementation using an optical tweezer setup with live samples of the motor protein kinesin; where regulation of forces below 1 pico Newton with errors below 10 percent is obtained while simultaneously providing real time estimates of motor motion.

math.OC↗

arXiv2016

Emergent Transport Properties of Molecular Motor Ensemble Affected by Single Motor Mutations

Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins - proteins converting chemical energy into kinetic energy. It is known that motor proteins work in teams enabling unidirectional and bidirectional transport of intracellular cargo over long distances. Disruptions of the underlying transport mechanisms, often caused by mutations that alter single motor characteristics, are known to cause neurodegenerative diseases. For example, phosphorylation of kinesin motor domain at the serine residue is implicated in Huntington's disease, with a recent study of phosphorylated and phosphomimetic serine residues indicating lowered single motor stalling forces. In this article we report the effects of mutations of this nature on transport properties of cargo carried by multiple wild-type and mutant motors. Results indicate that mutants with altered stall forces might determine the average velocity and run-length even when they are outnumbered by wild type motors in the ensemble. It is shown that mutants gain a competitive advantage and lead to an increase in expected run-length when load on the cargo is in the vicinity of the mutant's stalling force or a multiple of its stalling force. A separate contribution of this article is the development of a semi-analytic method to analyze transport of cargo by multiple motors of multiple types. The technique determines transition rates between various relative configurations of motors carrying the cargo using the transition rates between various absolute configurations. This enables exact computation of average velocity and run-length. It can also be used to introduce alterations of various single motor parameters to model a mutation and to deduce effects of such alterations on the transport of a common cargo by multiple motors. Our method is easily implementable and we provide a software package for general use.

q-bio.SC↗