Backbone-dependent Rotamer Library Research Articles

The stability of transmembrane helices: a molecular dynamics study on the isolated helices of bacteriorhodopsin.

Bacteriorhodopsin (bR) continues to be a proven testing ground for the study of integral membrane proteins (IMPs). It is important to study the stability of the individual helices of bR, as they are postulated to exist as independently stable transmembrane helices (TMHs) and also for their utility as templates for modeling other IMPs with the postulated seven-helix bundle topology. Toward this purpose, the seven helices of bR have been studied by molecular dynamics simulation in this study. The suitability of using the backbone-dependent rotamer library of side-chain conformations arrived at from the data base of globular protein structures in the case TMHs has been tested by another set of 7 helix simulations with the side-chain orientations taken from this library. The influence of the residue's net charge on the helix stability was examined by simulating the helices III, IV, and VI (from both of the above sets of helices) with zero net charge on the side chains. The results of these 20 simulations demonstrate in general the stability of the isolated helices of bR in conformity with the two-stage hypothesis of IMP folding. However, the helices I, II, V, and VII are more stable than the other three helices. The helical nature of certain regions of III, IV, and VI are influenced by factors such as the net charge and orientation of several residues. It is seen that the residues Arg, Lys, Asp, and Glu (charged residues), and Ser, Thr, Gly, and Pro, play a crucial role in the stability of the helices of bR. The backbone-dependent rotamer library for the side chains is found to be suitable for the study of TMHs in IMP.

Bayesian statistical analysis of protein side-chain rotamer preferences.

We present a Bayesian statistical analysis of the conformations of side chains in proteins from the Protein Data Bank. This is an extension of the backbone-dependent rotamer library, and includes rotamer populations and average chi angles for a full range of phi, psi values. The Bayesian analysis used here provides a rigorous statistical method for taking account of varying amounts of data. Bayesian statistics requires the assumption of a prior distribution for parameters over their range of possible values. This prior distribution can be derived from previous data or from pooling some of the present data. The prior distribution is combined with the data to form the posterior distribution, which is a compromise between the prior distribution and the data. For the chi 2, chi 3, and chi 4 rotamer prior distributions, we assume that the probability of each rotamer type is dependent only on the previous chi rotamer in the chain. For the backbone-dependence of the chi 1 rotamers, we derive prior distributions from the product of the phi-dependent and psi-dependent probabilities. Molecular mechanics calculations with the CHARMM22 potential show a strong similarity with the experimental distributions, indicating that proteins attain their lowest energy rotamers with respect to local backbone-side-chain interactions. The new library is suitable for use in homology modeling, protein folding simulations, and the refinement of X-ray and NMR structures.

Prediction of protein side-chain rotamers from a backbone-dependent rotamer library: a new homology modeling tool

Modeling by homology is the most accurate computational method for translating an amino acid sequence into a protein structure. Homology modeling can be divided into two sub-problems, placing the polypeptide backbone and adding side-chains. We present a method for rapidly predicting the conformations of protein side-chains, starting from main-chain coordinates alone. The method involves using fewer than ten rotamers per residue from a backbone-dependent rotamer library and a search to remove steric conflicts. The method is initially tested on 299 high resolution crystal structures by rebuilding side-chains onto the experimentally determined backbone structures. A total of 77% of χ 1 and 66% of χ 1+2 dihedral angles are predicted within 40° of their crystal structure values. We then tested the method on the entire database of known structures in the Protein Data Bank. The predictive accuracy of the algorithm was strongly correlated with the resolution of the structures. In an effort to simulate a realistic homology modeling problem, 9424 homology models were created using three different modeling strategies. For prediction purposes, pairs of structures were identified which shared between 30% and 90% sequence identity. One strategy results in 82% of χ 1 and 72% χ 1+2 dihedral angles predicted within 40 degrees of the target crystal structure values, suggesting that movements of the backbone associated with this degree of sequence identity are not large enough to disrupt the predictive ability of our method for non-native backbones. These results compared favorably with existing methods over a comprehensive data set.

Comparing theoretical and experimental backbone-dependent sidechain conformational preferences for linear, branched, aromatic and polar residues

Abstract An Ecepp-3 conformational study based on a φ-ψ grid search with sidechain minimization was carried out on the N-acetyl N′-methyl amides of four representative amino acids: Met, Phe, Ile, and Ser, and the distribution of ξ 1 backbone-dependent rotamer preferences was compared with the similar distribution obtained from the backbone-dependent rotamer library for proteins developed by Dunbrack and Karplus (J. Mol. Biol. 230 (1993) 543). The experimental distribution is best reproduced theoretically in the case of the linear sidechain of Met, reasonably well for the bulky sidechains of the aromatic Phe and asymmetrically β-branched Ile, and only partially for the short polar sidechain of Ser. In the case of the Ser dipeptide the difference is accounted for by the missing H bonds.

Backbone-dependent Rotamer Library for Proteins Application to Side-chain Prediction

A backbone-dependent rotamer library for amino acid side-chains is developed and used for constructing protein side-chain conformations from the main-chain co-ordinates. The rotamer library is obtained from 132 protein chains in the Brookhaven Protein Database. A grid of 20° by 20° blocks for the main-chain angles φ,ψ is used in the rotamer library. Significant correlations are found between side-chain dihedral angle probabilities and backbone φ,ψ values. These probabilities are used to place the side-chain on the known backbone in the test application for six proteins for which high-resolution crystal structures are available. A minimization scheme is used to reorient side-chains that conflict with the backbone or other side-chains after the initial placement. The initial placement yields 59% of both χ1 and χ2 values in the correct position (to within 40°) for thermolysin to 81% for crambin. After refinement the values range from 61% (lysozyme) to 89% (crambin). It is evident from the results that a single protein does not adequately test a prediction scheme.The computation time required by the method scales linearly with the number of side-chains. An initial prediction from the library takes only a few seconds of computer time, while the iterative refinement takes on the order of hours. The method is automated and can easily be applied to aid experimental side-chain determinations and homology modeling. The high degree of correlation between backbone and side-chain conformations may introduce a simplification in the protein folding process by reducing the available conformational space.