DOI: 10.1073/pnas.0409387102. Structural dynamics of the <i>lac</i> repressor–DNA complex revealed by a multiscale simulation

Structural dynamics of the lac repressor–DNA complex revealed by a multiscale simulation

10.1073/pnas.0409387102

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

A multiscale simulation of a complex between the lac repressor protein (LacI) and a 107-bp-long DNA segment is reported. The complex between the repressor and two operator DNA segments is described by all-atom molecular dynamics; the size of the simulated system comprises either 226,000 or 314,000 atoms. The DNA loop connecting the operators is modeled as a continuous elastic ribbon, described mathematically by the nonlinear Kirchhoff differential equations with boundary conditions obtained from the coordinates of the terminal base pairs of each operator. The forces stemming from the looped DNA are included in the molecular dynamics simulations; the loop structure and the forces are continuously recomputed because the protein motions during the simulations shift the operators and the presumed termini of the loop. The simulations reveal the structural dynamics of the LacI–DNA complex in unprecedented detail. The multiple domains of LacI exhibit remarkable structural stability during the simulation, moving much like rigid bodies. LacI is shown to absorb the strain from the looped DNA mainly through its mobile DNA-binding head groups. Even with large fluctuating forces applied, the head groups tilt strongly and keep their grip on the operator DNA, while the remainder of the protein retains its V-shaped structure. A simulated opening of the cleft of LacI by 500-pN forces revealed the interactions responsible for locking LacI in the V-conformation.

Bibliography

Villa, E., Balaeff, A., & Schulten, K. (2005). Structural dynamics of the lac repressorâDNA complex revealed by a multiscale simulation. Proceedings of the National Academy of Sciences, 102(19), 6783â6788.

Authors 3

Elizabeth Villa (first)
Alexander Balaeff (additional)
Klaus Schulten (additional)

References 32 Referenced 121

Berg J. M. Tymoczko J. L. & Stryer L. (2002) Biochemistry (Freeman New York) 5th Ed.
10.1128/mr.56.1.123-136.1992
10.1146/annurev.bi.61.070192.001215
10.1126/science.271.5253.1247
10.1002/j.1460-2075.1990.tb08199.x
10.1126/science.7792597
10.1038/73317
10.1016/S0006-3495(03)74929-7
10.1126/science.276.5315.1109
10.1137/040604789
10.1146/annurev.matsci.32.122001.102202
10.1063/1.1356001
10.1016/0959-440X(95)80083-2
10.1016/S0959-440X(96)80082-0
10.1103/PhysRevLett.83.4900
10.1016/j.str.2003.12.004
10.1016/S0969-2126(00)88339-2
10.1016/0263-7855(96)00018-5
10.1126/science.7761829
10.1006/jcph.1999.6201
10.1021/jp973084f
10.1063/1.467468
10.1063/1.477414
10.1098/rsta.2004.1384
10.1146/annurev.bb.17.060188.001405
10.1126/science.271.5257.1835
10.1016/S0959-440X(00)00194-9
10.1038/347631a0
10.1038/nature01160
Dominy, B. N. & Brooks, C. L., III (2001) J. Comp. Chem. 23, 147–160. / J. Comp. Chem. (2001)
Howard J. (2001) Mechanics of Motor Proteins and the Cytoskeleton (Sinauer Sunderland MA).
10.1016/S0022-2836(02)01001-X

Dates

Type	When
Created	20 years, 3 months ago (April 29, 2005, 8:34 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 1:30 p.m.)
Indexed	3 weeks, 6 days ago (July 28, 2025, 2:41 a.m.)
Issued	20 years, 3 months ago (April 29, 2005)
Published	20 years, 3 months ago (April 29, 2005)
Published Online	20 years, 3 months ago (April 29, 2005)
Published Print	20 years, 3 months ago (May 10, 2005)

Funders 0

None

BibTeX

@article{Villa_2005, title={Structural dynamics of the lac repressor–DNA complex revealed by a multiscale simulation}, volume={102}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0409387102}, DOI={10.1073/pnas.0409387102}, number={19}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Villa, Elizabeth and Balaeff, Alexander and Schulten, Klaus}, year={2005}, month=apr, pages={6783–6788} }

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