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The Interplay between Phase Separation and Gene-Enhancer Communication: A Theoretical Study.

ABSTRACT: The phase separation occurring in a system of mutually interacting proteins that can bind on specific sites of a chromatin fiber is investigated here. This is achieved by means of extensive molecular dynamics simulations of a simple polymer model that includes regulatory proteins as interacting spherical particles. Our interest is particularly focused on the role played by phase separation in the formation of molecule aggregates that can join distant regulatory elements, such as gene promoters and enhancers, along the DNA. We find that the overall equilibrium state of the system resulting from the mutual interplay between binding molecules and chromatin can lead, under suitable conditions that depend on molecules concentration, molecule-molecule, and molecule-DNA interactions, to the formation of phase-separated molecular clusters, allowing robust contacts between regulatory sites. Vice versa, the presence of regulatory sites can promote the phase-separation process. Different dynamical regimes can generate the enhancer-promoter contact, either by cluster nucleation at binding sites or by bulk spontaneous formation of the mediating cluster to which binding sites are successively attracted. The possibility that such processes can explain experimental live-cell imaging data measuring distances between regulatory sites during time is also discussed.

SUBMITTER: Chiariello AM

PROVIDER: S-EPMC7451901 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The potential energy surface (PES) of the C6H5 + NH2 reaction has been investigated by using ab initio CCSD(T)//B3LYP/6-311++G(3df,2p) calculations. The conventional transition-state theory (TST) and the variable reaction coordinate-TST (VRC-TST) have been used to predict the rate constants for the channels possessing tight and barrierless transition states, respectively. The Rice-Ramsperger-Kassel-Marcus/Master equation (RRKM/ME) theory has been utilized to determine the pressure-dependent rate constants for these reactions. The PES shows that the reaction begins with an exothermic barrierless addition of NH2 to C6H5 producing the vital intermediate state, namely, aniline (C6H5NH2, IS1). Once IS1 is generated, it can further isomerize to various intermediate states, which can give rise to different products, including PR4 (4,5,6-trihydro-1-amino phenyl + H2), PR5 (3,4,5,6-tetrahydro phenyl + NH3), PR6 (2,3,5,6-tetrahydro-1-imidogen phenyl + H2), PR9 (3,4,5,6-tetrahydro-1-imidogen phenyl + H2), and PR10 (2,5,6-trihydro-1-amino phenyl + H2), of which the most stable product, PR5, was formed by the most favorable channel going through the two advantageous transition states T1/11 (-28.9 kcal/mol) and T11P5 (-21.5 kcal/mol). The calculated rate constants for the low-energy channel, 1.37 × 10-9 and 2.16 × 10-11 cm3 molecule-1 s-1 at T = 300, P = 1 Torr and T = 2000 K, P = 760 Torr, respectively, show that the title reaction is almost pressure- and temperature-dependent. The negative temperature-dependent rate coefficients can be expressed in the modified Arrhenius form of k 1 = 8.54 × 1013 T -7.20 exp (-7.07 kcal·mol-1/RT) and k 2 = 2.42 × 1015 T -7.61 exp (-7.75 kcal·mol-1/RT) at 1 and 10 Torr, respectively, and in the temperature range of 300-2000 K. The forward and reverse rate coefficients as well as the high-pressure equilibrium constants of the C6H5 + NH2 ↔ IS1 process were also predicted; their values revealed that its kinetics do not depend on pressure at low temperature but strongly depend on pressure at high temperature. Moreover, the predicted formation enthalpies of reactants and the enthalpy changes of some channels are in good agreement with the experimental results.

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The Interplay between Phase Separation and Gene-Enhancer Communication: A Theoretical Study.

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