Multiscale modeling of macromolecular conformational changes combining concepts from rigidity and elastic network theory

被引:66
作者
Ahmed, Aqeel [1 ]
Gohlke, Holger [1 ]
机构
[1] Univ Frankfurt, Dept Biol & Comp Sci, D-6000 Frankfurt, Germany
关键词
normal mode analysis; rigidity/flexibility; collective motions; vibrations; proteins; induced fit;
D O I
10.1002/prot.20907
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The development of a two-step approach for multiscale modeling of macromolecular conformational changes is based on recent developments in rigidity and elastic network theory. In the first step, static properties of the macromolecule are determined by decomposing the molecule into rigid clusters by using the graph-theoretical approach FIRST and an all-atom representation of the protein. In this way, rigid clusters are not limited to consist of residues adjacent in sequence or secondary structure elements as in previous studies. Furthermore, flexible links between rigid clusters are identified and can be modeled as such subsequently. In the second step, dynamical properties of the molecule are revealed by the rotations-translations of blocks approach (RTB) using an elastic network model representation of the coarse-grained protein. In this step, only rigid body motions are allowed for rigid clusters, whereas links between them are treated as fully flexible. The approach was tested on a data set of 10 proteins that showed conformational changes on ligand binding. For efficiency, coarse-graining the protein results in a remarkable reduction of memory requirements and computational times by factors of 9 and 27 on average and up to 25 and 125, respectively. For accuracy, directions and magnitudes of motions predicted by our approach agree well with experimentally determined ones, despite embracing in extreme cases >50% of the protein into one rigid cluster. In fact, the results of our method are in general comparable with when no or a uniform coarse-graining is applied; and the results are superior if the movement is dominated by loop or fragment motions. This finding indicates that explicitly distinguishing between flexible and rigid regions is advantageous when using a simplified protein representation in the second step. Finally, motions of atoms in rigid clusters are also well predicted by our approach, which points to the need to consider mobile protein regions in addition to flexible ones when modeling correlated motions. Proteins 2006;63:1038-1051. (c) 2006 WiIey-Liss, Inc.
引用
收藏
页码:1038 / 1051
页数:14
相关论文
共 71 条
[1]   OLIGOMERIC REARRANGEMENT OF TICK-BORNE ENCEPHALITIS-VIRUS ENVELOPE PROTEINS INDUCED BY AN ACIDIC PH [J].
ALLISON, SL ;
SCHALICH, J ;
STIASNY, K ;
MANDL, CW ;
KUNZ, C ;
HEINZ, FX .
JOURNAL OF VIROLOGY, 1995, 69 (02) :695-700
[2]   Increased backbone mobility in β-barrel enhances entropy gain driving binding of N-TIMP-1 to MMP-3 [J].
Arumugam, S ;
Gao, GH ;
Patton, BL ;
Semenchenko, V ;
Brew, K ;
Van Doren, SR .
JOURNAL OF MOLECULAR BIOLOGY, 2003, 327 (03) :719-734
[3]   Anisotropy of fluctuation dynamics of proteins with an elastic network model [J].
Atilgan, AR ;
Durell, SR ;
Jernigan, RL ;
Demirel, MC ;
Keskin, O ;
Bahar, I .
BIOPHYSICAL JOURNAL, 2001, 80 (01) :505-515
[4]   Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential [J].
Bahar, I ;
Atilgan, AR ;
Erman, B .
FOLDING & DESIGN, 1997, 2 (03) :173-181
[5]   The Protein Data Bank [J].
Berman, HM ;
Westbrook, J ;
Feng, Z ;
Gilliland, G ;
Bhat, TN ;
Weissig, H ;
Shindyalov, IN ;
Bourne, PE .
NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242
[6]   HARMONIC DYNAMICS OF PROTEINS - NORMAL-MODES AND FLUCTUATIONS IN BOVINE PANCREATIC TRYPSIN-INHIBITOR [J].
BROOKS, B ;
KARPLUS, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1983, 80 (21) :6571-6575
[7]  
BRUSCHWEILER R, 1995, J CHEM PHYS, V102, P3396, DOI 10.1063/1.469213
[8]   Changes in flexibility upon binding: Application of the self-consistent pair contact probability method to protein-protein interactions [J].
Canino, LS ;
Shen, TY ;
McCammon, JA .
JOURNAL OF CHEMICAL PHYSICS, 2002, 117 (21) :9927-9933
[9]   Protein flexibility and drug design: how to hit a moving target [J].
Carlson, HA .
CURRENT OPINION IN CHEMICAL BIOLOGY, 2002, 6 (04) :447-452
[10]   NORMAL-MODE ANALYSIS OF PROTEIN DYNAMICS [J].
CASE, DA .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 1994, 4 (02) :285-290