Extensive Conformational Heterogeneity within Protein Cores

被引:33
作者
Bowman, Gregory R. [1 ,2 ]
Geissler, Phillip L. [2 ,3 ]
机构
[1] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA
[3] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA
关键词
MOLECULAR SIMULATION; BACKBONE DYNAMICS; ENERGY LANDSCAPE; HUMAN UBIQUITIN; NMR RELAXATION; SIDE-CHAINS; N-15; FLUCTUATIONS; ANISOTROPY; ALLOSTERY;
D O I
10.1021/jp4105823
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Basic principles of statistical mechanics require that proteins sample an ensemble of conformations at any nonzero temperature. However, it is still common to treat the crystallographic structure of a protein as the structure of its native state, largely because high-resolution structural characterization of protein flexibility remains a profound challenge. To assess the typical degree of conformational heterogeneity within folded proteins, we construct Markov state models describing the thermodynamics and kinetics of proteins ranging from 72 to 263 residues in length. Each of these models is built from hundreds of microseconds of atomically detailed molecular dynamics simulations. Examination of the side-chain degrees of freedom reveals that almost every residue visits at least two rotameric states over this time frame, with rotamer transition rates spanning a wide range of time scales (from nanoseconds to tens of microseconds). We also report substantial backbone dynamics on time scales longer than are typically addressed by experimental measures of protein flexibility, such as NMR order parameters. Finally, we demonstrate that these extensive rearrangements are consistent with NMR and crystallographic data, which supports the validity of our models. Altogether, these results depict the interior of proteins not as well-ordered solids, as is often imagined, but instead as dense fluids, which undergo substantial structural fluctuations despite their high packing fraction.
引用
收藏
页码:6417 / 6423
页数:7
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