TY - JOUR
T1 - Excluded volume in protein side-chain packing
AU - Kussell, Edo
AU - Shimada, Jun
AU - Shakhnovich, Eugene I.
N1 - Funding Information:
We are grateful for stimulating discussions with Gabriel Berriz, Alexey Finkelstein, Leonid Mirny, and Michael Morrissey, and especially thank Kirk Doran for his assistance. E.K. thanks Kate Currie, Efrat Kussell, Amber Musser, and Arwen O’Reilly for making this paper possible by typing for him when he could not. Financial support from NIH (grant 52126) and NSF (graduate fellowship, E.K.) is acknowledged.
PY - 2001/8/3
Y1 - 2001/8/3
N2 - The excluded volume occupied by protein side-chains and the requirement of high packing density in the protein interior should severely limit the number of side-chain conformations compatible with a given native backbone. To examine the relationship between side-chain geometry and side-chain packing, we use an all-atom Monte Carlo simulation to sample the large space of side-chain conformations. We study three models of excluded volume and use umbrella sampling to effectively explore the entire space. We find that while excluded volume constraints reduce the size of conformational space by many orders of magnitude, the number of allowed conformations is still large. An average repacked conformation has 20% of its χ angles in a non-native state, a marked reduction from the expected 67% in the absence of excluded volume. Interestingly, well-packed conformations with up to 50% non-native χ angles exist. The repacked conformations have native packing density as measured by a standard Voronoi procedure. Entropy is distributed non-uniformly over positions, and we partially explain the observed distribution using rotamer probabilities derived from the Protein Data Bank database. In several cases, native rotamers that occur infrequently in the database are seen with high probability in our simulation, indicating that sequence-specific excluded volume interactions can stabilize rotamers that are rare for a given backbone. In spite of our finding that 65% of the native rotamers and 85% of χ1 angles can be predicted correctly on the basis of excluded volume only, 95% of positions can accommodate more than one rotamer in simulation. We estimate that, in order to quench the side-chain entropy observed in the presence of excluded volume interactions, other interactions (hydrophobic, polar, electrostatic) must provide an additional stabilization of at least 0.6 kT per residue in order to single out the native state.
AB - The excluded volume occupied by protein side-chains and the requirement of high packing density in the protein interior should severely limit the number of side-chain conformations compatible with a given native backbone. To examine the relationship between side-chain geometry and side-chain packing, we use an all-atom Monte Carlo simulation to sample the large space of side-chain conformations. We study three models of excluded volume and use umbrella sampling to effectively explore the entire space. We find that while excluded volume constraints reduce the size of conformational space by many orders of magnitude, the number of allowed conformations is still large. An average repacked conformation has 20% of its χ angles in a non-native state, a marked reduction from the expected 67% in the absence of excluded volume. Interestingly, well-packed conformations with up to 50% non-native χ angles exist. The repacked conformations have native packing density as measured by a standard Voronoi procedure. Entropy is distributed non-uniformly over positions, and we partially explain the observed distribution using rotamer probabilities derived from the Protein Data Bank database. In several cases, native rotamers that occur infrequently in the database are seen with high probability in our simulation, indicating that sequence-specific excluded volume interactions can stabilize rotamers that are rare for a given backbone. In spite of our finding that 65% of the native rotamers and 85% of χ1 angles can be predicted correctly on the basis of excluded volume only, 95% of positions can accommodate more than one rotamer in simulation. We estimate that, in order to quench the side-chain entropy observed in the presence of excluded volume interactions, other interactions (hydrophobic, polar, electrostatic) must provide an additional stabilization of at least 0.6 kT per residue in order to single out the native state.
KW - Packing density
KW - Protein folding
KW - Protein structure prediction
KW - Side-chain packing
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U2 - 10.1006/jmbi.2001.4846
DO - 10.1006/jmbi.2001.4846
M3 - Article
C2 - 11469867
AN - SCOPUS:0035800653
SN - 0022-2836
VL - 311
SP - 183
EP - 193
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 1
ER -