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Development of a general theoretical framework and the fastest (in the world) computational algorithm capable of predicting the conformation of DNA and changes in its interaction with DNA-binding proteins under mechanical and geometric constraints at the single-molecule and mesoscale levels

  • Date: 2018
  • Institution: Mechanobiology Institute (Singapore)
  • Authors: Artem Efremov, Ladislav Hovan, Yan Jie
  • Aim of study: Organization and maintenance of the chromosomal DNA in living cells depends on the DNA interactions with a plethora of DNA-binding proteins. Formation of nucleoprotein complexes on DNA by such proteins is frequently subject to force and torque constraints. Although the existing experimental techniques allow such mechanical constraints to be imposed on individual DNA biopolymers, their precise effect on the regulation of DNA-protein interactions is still not fully understood due to the lack of systematic theoretical methods able to interpret complex experimental observations. To fill this gap, I have developed a general theoretical framework based on the transfer-matrix calculations that can be used to accurately describe behaviour of DNA-protein interactions under force and torque constraints.

Major results: The developed theoretical approach has made it possible to quickly evaluate changes in the DNA conformation due to formation of nucleoprotein complexes in a wide range of mechanical constraints applied to DNA. Our method was found to be six orders of magnitude faster than Brownian / molecular dynamics simulation and Metropolis-Monte Carlo computation algorithms, which are used to model DNA behaviour under mechanical constraints in the presence of DNA-binding proteins. As shown in our study, a very high computational speed of the developed method allows quickly and easily fit complex data collected in single-molecule experiments, providing important information about the DNA-binding properties of proteins and the role of mechanical constraints in their regulation.

Contribution to the research field: A leading researcher in the polymer physics field, Prof. Peter G. Wolynes (Rice University, USA), noted in his article that the method developed in our study “… has proved useful in formulating an explicit sequence-dependent model of the mechanical coupling of the binding of proteins to the local DNA elastic modulus as well as a general theoretical framework for DNA mechanics with various mechanical constraints.”