- Proceedings
- Open Access
A protein-dependent side-chain rotamer library
- Md Shariful Islam Bhuyan^{1} and
- Xin Gao^{1}Email author
https://doi.org/10.1186/1471-2105-12-S14-S10
© Bhuyan and Gao; licensee BioMed Central Ltd. 2011
- Published: 14 December 2011
Abstract
Background
Protein side-chain packing problem has remained one of the key open problems in bioinformatics. The three main components of protein side-chain prediction methods are a rotamer library, an energy function and a search algorithm. Rotamer libraries summarize the existing knowledge of the experimentally determined structures quantitatively. Depending on how much contextual information is encoded, there are backbone-independent rotamer libraries and backbone-dependent rotamer libraries. Backbone-independent libraries only encode sequential information, whereas backbone-dependent libraries encode both sequential and locally structural information. However, side-chain conformations are determined by spatially local information, rather than sequentially local information. Since in the side-chain prediction problem, the backbone structure is given, spatially local information should ideally be encoded into the rotamer libraries.
Methods
In this paper, we propose a new type of backbone-dependent rotamer library, which encodes structural information of all the spatially neighboring residues. We call it protein-dependent rotamer libraries. Given any rotamer library and a protein backbone structure, we first model the protein structure as a Markov random field. Then the marginal distributions are estimated by the inference algorithms, without doing global optimization or search. The rotamers from the given library are then re-ranked and associated with the updated probabilities.
Results
Experimental results demonstrate that the proposed protein-dependent libraries significantly outperform the widely used backbone-dependent libraries in terms of the side-chain prediction accuracy and the rotamer ranking ability. Furthermore, without global optimization/search, the side-chain prediction power of the protein-dependent library is still comparable to the global-search-based side-chain prediction methods.
Keywords
- Marginal Distribution
- Markov Random Field
- Tree Decomposition
- Interaction Graph
- Inference Algorithm
Background
Protein molecules are indispensable in most of the cellular functions, such as metabolism, gene regulation, signal transduction, and cell cycle. The capability of being such a diverse worker arises mainly due to their structures. Therefore, predicting protein structures accurately is important for both function determination and protein design purposes.
Side-chain prediction
Due to the difficulty of predicting complete protein structures simultaneously, structure determination remains as a multi-phase task. There are different sub-tasks including backbone prediction, side-chain prediction, loop modeling, and refinement. In this paper, we focus on the prediction of the side-chain conformation for a given backbone structure, i.e., protein side-chain prediction problem. By using the concept of rotamers, this is essentially the problem of correct rotamer assignment for every amino acid so that the overall structure is thermodynamically stable. It is assumed that stability comes at low internal energy states. That is why the problem of side-chain prediction is traditionally considered to be an optimization problem which strives to find a rotamer assignment which will minimize the total internal energy of the protein molecule. Since in most cases rotamers are discrete values, the problem is reduced to a combinatorial search problem in previous work [2–5].
To solve an optimization problem, two components are needed, the objective function which has to be maximized/minimized and the search strategy which tries to search for the global maximum/minimum. In side-chain prediction, the rotamer solution space is exponential in the size of the protein and the objective function, which is an energy function in this case, has numerous local minima. This combination dictates people to prioritize the candidate rotamers to design a practical search strategy, which is the place where rotamer libraries come to play a role. In the past three decades there have been lots of studies in each direction. Different kinds of energy functions have been tried and developed [4–10]. In the domain of search strategy, a broad range of combinatorial search algorithms, both exact [11–15] and approximate [16–20] ones, have been applied. To incorporate prior knowledge, different kinds of rotamer libraries have been developed. In this paper, we propose a novel idea in the context of rotamer library.
Rotamer library
Rotamer libraries [16, 21–24] are important components not only in side-chain prediction but also in several other areas including protein design. They summarize the existing knowledge of the experimentally determined structures quantitatively. Along with other information, rotamer libraries contain estimated probabilities of the discrete conformations of side-chain dihedral angles calculated from the structure databases. Depending on how much contextual information is taken into account, there can be different kinds of libraries. Initially the libraries consider only amino acid specific context and the probabilities are given for rotamers of different amino acids [25–30]. They are called backbone independent rotamer libraries. However, the discriminative power of the backbone independent libraries is not enough to eliminate sufficient amount of rotamer choices. Therefore, the backbone dependent rotamer libraries have been introduced [1, 21–24, 31–36]. These libraries consider the local backbone context through the ϕ and ψ angles along with the amino acid information. Backbone dependent rotamer libraries have been demonstrated to be able to boost the accuracy of a side-chain predictor equipped with the global optimizer over energy function landscape and guide them to avoid local minima [33]. Theoretically, the more context-specific information the library can encode, the more precise rotamer choices it can deliver. In this paper, we combine the general purpose backbone-dependent rotamer library with the detailed backbone atom coordinates of a specific protein, to introduce a protein-dependent rotamer library, without global optimization or search. To the best of our knowledge, this is a novel idea in the domain of rotamer library. For traditional backbone-dependent rotamer library, for a certain amino acid, the probability of its certain rotamer depends only on the local backbone ϕ and ψ angles. In our case the probabilities of two different rotamers of the same amino acid with the same ϕ and ψ angles can have different marginal distributions depending on their interactions with the surrounding environments.
Markov random field model
Given a backbone dependent rotamer library, e.g., Dun-brack’s libraries published in the year of 2002 or 2010, and the backbone structure of a query protein, we first model the backbone and side-chain structures of the protein in Markov random field (MRF), where the residues are modeled as vertices of the interaction graph. We then employ widely used energy functions, e.g., Scwrl3 [4] energy function, to set up the potential for inference algorithms, e.g., sum-product belief propagation, to compute the marginal distributions of the residue-specific rotamers. In this way, all the rotamers are re-ranked for each residue in the query protein, according to the marginal distributions. We will demonstrate that this re-ranking can significantly improve the accuracy of the input backbone dependent rotamer library, which can hopefully benefit the global search algorithms for side-chain packing, such as the dead-end-elimination algorithm proposed in [11] and the tree decomposition algorithm proposed in [2, 3].
One thing to notice is that modeling protein structures using probabilistic graphical models is not new [37–40]. Kamisetty et al. modeled protein structures by MRF and applied generalized belief propagation (GBP) to compute the free energy of a protein structure [37]. Our graphical model of protein structures is similar to their model. However, our focus is to calculate the marginal distributions and re-rank the rotamers, without calculating the free energy. We will demonstrate that loopy belief propagation (LBP) outperforms GBP for this purpose. Besides, we have encoded an energy function that is more suitable for re-ranking the rotamers than the ROSETTA energy function used in [37]. Yanover et al. modeled protein structures by conditional random field (CRF) and applied max-product belief propagation (BP) algorithms for side-chain prediction [39]. Our work is different from theirs in several ways. Firstly, their purpose is to apply max-product BP as a global search algorithm, which means they are interested in finding the optimal rotamer combination of all the side chains simultaneously, i.e., the combination that corresponds to the maximum joint probability. Therefore, their method is a side-chain predictor by itself, which can hardly be used by more powerful search algorithms, such as the one proposed recently in Scwrl4 [5]. We model protein structures as a MRF and apply sum-product BP, which provides the detailed marginal distribution for each side-chain, without global optimization. That means, if one selects the highest probability rotamer for each side-chain in our method, it may not yield a valid side-chain packing due to atomic clashes. Therefore, our method should be considered as a protein-dependent rotamer library which serves as the input for global search algorithms. Secondly, [39] used the ROSETTA energy function and demonstrated that the tree re-weighted BP algorithm performed very well to minimize and learn this energy function. However, our results demonstrate that this is not a general case. We use the simpler Scwrl3 [4] energy function and for that tree re-weighted BP does not perform better than the other BP algorithms.
Another thing to notice is that our protein-dependent rotamer library computes the marginal distributions of all the side-chain torsion angles (up to four) for a specific residue position, rather than considering them independently. This makes sense due to the high correlation between the torsion angles belong to the same amino acid.
Contributions
- 1.
We introduce the idea of protein-dependent rotamer library and show the superiority of this library with respect to the widely used backbone-dependent rotamer libraries [1, 24] in terms of both the accuracy of rotamer ranking and the probability assigned to the correct rotamers, on a large benchmark data set proposed recently by [5].
- 2.
We model the protein structure as a MRF, encode the Scwrl3 energy function, and compare different sum-product BP algorithms to re-rank the rotamers. Our method does not contain a learning process, which is more likely to perform consistently well on other data sets and other energy functions.
- 3.
The proposed protein-dependent rotamer library can be easily used as a side-chain predictor if we threshold each marginal distribution to its most probable rotamer. We compare our library with the most widely used side-chain predictors [2–5] and demonstrate that the accuracy is acceptable without using any global search/optimization techniques. Moreover, our library gives a probability distribution among rotamer choices instead of producing a single choice.
Methods
We use the backbone structure of a protein in PDB format as our input. The output is a rotamer library with a format similar to that of Dunbrack’s library [1]. In Dunbrack’s library for each combination of an amino acid and a particular (ϕ, ψ) backbone dihedral conformation, there is one and only one distribution of rotamer conformations. However, in our generated output, for every amino acid in the protein sequence we have a distribution. This implies we can have distinct marginal distributions for same type of amino acids with similar (ϕ, ψ) angles. The distributions differ because of the consideration of surrounding environment of a certain amino acid.
When a protein backbone conformation is given, our method constructs an interaction graph where each residue is a vertex. We place an edge between a pair of residues if at least one pair of atoms from them is found to be closer than a minimum threshold. After that we set up the energy potentials for each node as well as each edge. Using the potentials, an inference algorithm is applied to calculate the marginal distributions of rotamers choices.
- 1.
Creating the interaction graph
- 2.
Setting up energy potentials
- 3.
Inferring marginal distributions
Creating the interaction graph
Setting potentials
Here E_{ scij } (r_{ im }, r_{ jn }) denotes the summation of all pair-wise energy components resulting from the interaction between the side chain atoms of residue x_{ i } in rotameric state r_{ im } and the side chain atoms of residue x_{ j } in rotameric state r_{ jn }. For calculation of energy of an atomic pair we use the SCWRL3.0 function described above. The E_{ hb }(x_{ i }, x_{ j }) denotes the energy due to hydrogen bonding between residue pair. We use the hydrogen bond component of the ROSETTA energy function.
Inferring marginal distributions
After assigning all the vertex and edge potentials, the interaction graph becomes a MRF. To re-rank the rotamer choices for each side-chain in this MRF, marginal distributions need to be computed. We employ different inference algorithms such as loopy belief propagation (LBP), generalized belief propagation (GBP) with a region graph, mean field approximation (MF) and tree re-weighted belief propagation (TRBP). Among them, LBP performs better than others, as we will show in the Results section. We give a brief description of them in the following.
Loopy belief propagation
The first equation intuitively captures the marginal likelihood by combining old belief of a vertex and the old incoming messages sent by all of its neighbors. From this information a vertex can calculate new outgoing messages which capture an estimation of the marginal distribution of destination neighbors by combining old belief of the source vertex and the beliefs of source vertex estimated by all of its neighbors except the destination. Specifically, b(x_{ i }) denotes the approximated marginal distribution of the node x_{ i }. The set of all the neighbors of x_{ i } is represented by N(i). m_{ ij }(x_{ j }) indicates a message sent from node x_{ i } to node x_{ j } and contains a marginal distribution of node x_{ j } estimated by node x_{ i }. We use the sum-product algorithm for message passing where each node collects messages from all of its neighboring nodes and calculates new messages for each of its neighbors by taking the product of messages sent by other neighbors and summing over its current distribution.
Other inference algorithms
Generalized belief propagation is a family of approximate inference algorithms which divide the original graph into several regions to decrease the computational complexity. However, the belief expression and message update rule remain same with one subtle difference. Due to the division among regions one node can occur in multiple regions. So, we need to set weights for the contributions of these border nodes to different regions so that their overall contributions remain correct.
After computing the marginal distribution of side-chain conformation for every vertex, the rotamers in the input rotamer library are re-ranked for each side-chain. We create a protein-dependent rotamer library according to the same structure of the input backbone-dependent rotamer library which can be used by other global optimization algorithms.
Dataset and software
To show the efficacy of our idea, we use the same data set of 379 proteins used in the Scwrl4 [5] paper. This is a larger and more recent data set comparing to the ones used in [2, 4]. After downloading the PDB files, there are 355 of them which do not contain any duplicate backbone atoms. For this set we run our program and construct the protein-dependent rotamer library, then compare the performance with two other widely used backbone-dependent rotamer libraries [1, 24]. For calculating actual dihedral angles from the original PDB files, we use the program Dangle [41]. To create the interaction graph of the protein we use the molecular biology toolkit [42]. Please note that since our method does not involve any training process, we do not subdivide the data set.
Results
In this section, we evaluate the performance of our proposed protein-dependent rotamer library. First of all, we compare the side-chain packing power of our library and the widely used backbone-dependent libraries [1, 24]. For our protein-dependent library, we threshold the marginal distribution of each side-chain to its most probably rotamer, which is considered as the prediction of our library for side-chain packing purpose. For the backbone-dependent libraries, we select the rotamer with the highest probability as the prediction. Please note that neither our library nor the backbone-dependent libraries involve global optimization. However, strong side-chain packing power gives more potential for the global optimization/search algorithms to benefit from the library. Secondly, we evaluate the re-ranking accuracy of our protein-dependent rotamer library. We compare both the average rank of the first correct rotamers and the average probability of finding correct rotamers within the top 1, 2 and 3 rotamers, respectively. A lower average rank and a higher probability can clearly reduce the search space of the following global optimization/search algorithms and boost the likelihood of such algorithms to pack side-chains correctly. Finally, we compare the accuracy and the speed of the four inference algorithms.
To calculate the accuracy of a rotamer choice, the most widely used criterion is used, i.e., if the mean dihedral angle of this rotamer is within 40 degree of the actual dihedral angle, this rotamer is considered to be correct; otherwise, it is considered to be wrong. For χ_{1+2} to be correct, both χ_{1} and χ_{2} have to be correct. We judge the correctness of χ_{1+2+3} and χ_{1+2+3+4} similarly.
Performance on side-chain prediction
We first evaluate the side-chain packing power of our protein-dependent rotamer library. We choose the widely used backbone-dependent rotamer libraries proposed by Dunbrack’s lab in 2002 and 2010 [1, 24] for comparison. The backbone-dependent library is used as input for our method and the corresponding rotamers are re-ranked according to the marginal distributions. For both our protein-dependent libraries and the backbone-dependent libraries, the rotamer with the highest probability for each side-chain is considered as the prediction by the corresponding library. The predictions are then compared with the real side-chain angles to calculate the accuracy.
In this experiment, we use LBP as the inference algorithm, because as we will show later in this section, LBP outperforms the other three inference algorithms. Similar conclusion can be drawn if other inference algorithms are used.
Comparison of rotamer libraries for side-chain prediction
Amino acid | Dihedral angle | P10 | P02 | D10 | D02 |
---|---|---|---|---|---|
CYS | χ _{1} | 55.76 | 56.40 | 50.16 | 50.09 |
SER | χ _{1} | 67.34 | 67.13 | 61.94 | 61.84 |
THR | χ _{1} | 88.46 | 87.81 | 86.13 | 85.85 |
VAL | χ _{1} | 90.79 | 90.58 | 86.94 | 86.99 |
ASN | χ _{1} χ _{1+2} | 79.21 56.18 | 78.33 53.34 | 69.53 49.34 | 69.31 47.15 |
ASP | χ _{1} χ _{1+2} | 78.27 60.80 | 79.33 60.36 | 72.47 57.16 | 73.12 56.18 |
HIS | χ _{1} χ _{1+2} | 79.12 45.01 | 77.93 43.29 | 63.33 33.33 | 62.06 32.86 |
ILE | χ _{1} χ _{1+2} | 91.56 77.71 | 91.18 77.20 | 86.91 68.18 | 87.05 68.02 |
LEU | χ _{1} χ _{1+2} | 84.21 74.22 | 83.70 73.19 | 74.89 68.59 | 74.20 67.94 |
PHE | χ _{1} χ _{1+2} | 88.26 53.17 | 86.90 52.28 | 72.95 42.00 | 73.03 42.23 |
PRO | χ _{1} χ _{1+2} | 83.11 79.01 | 82.20 78.19 | 80.96 76.70 | 80.92 76.74 |
TRP | χ _{1} χ _{1+2} | 69.42 55.60 | 68.06 50.40 | 53.49 35.61 | 53.01 34.98 |
TYR | χ _{1} χ _{1+2} | 87.29 51.30 | 86.38 51.59 | 72.64 42.67 | 72.68 43.18 |
GLN | χ _{1} χ _{1+2} χ _{1+2+3} | 72.37 50.25 25.71 | 70.67 48.91 23.08 | 63.62 34.05 17.20 | 62.47 38.72 16.03 |
GLU | χ _{1} χ _{1+2} χ _{1+2+3} | 67.46 47.86 26.17 | 66.39 46.65 25.03 | 62.36 41.97 21.21 | 61.71 41.14 20.48 |
MET | χ _{1} χ _{1+2} χ _{1+2+3} | 71.54 56.50 39.95 | 72.40 56.66 39.51 | 60.03 36.31 20.12 | 60.85 34.55 19.91 |
ARG | χ _{1} χ _{1+2} χ _{1+2+3} χ _{1+2+3+4} | 71.52 56.83 29.92 17.60 | 71.35 56.60 29.62 16.82 | 63.60 47.18 21.33 9.82 | 61.41 47.47 21.27 9.14 |
LYS | χ _{1} χ _{1+2} χ _{1+2+3} χ _{1+2+3+4} | 72.02 58.54 44.83 28.42 | 72.11 58.79 44.80 27.85 | 66.43 50.82 36.86 23.33 | 66.28 50.73 36.89 23.48 |
Overall | χ _{1} χ _{1+2} χ _{1+2+3} χ _{1+2+3+4} | 80.45 61.50 32.81 23.25 | 80.05 60.74 31.82 22.55 | 73.80 53.72 24.62 16.94 | 73.43 53.60 24.03 16.61 |
D02 Dunbrack’s backbone-dependent rotamer library proposed in 2002 [1]
D10 Improved version of Dunbrack’s library proposed in 2010 [24]
P02 Our protein-dependent rotamer library with D02 as the input library
P10 Our protein-dependent rotamer library with D10 as the input library
The accuracy of χ_{1} until χ_{4} (if there exists) for different amino acids as well as the overall accuracy of the four rotamer libraries is shown in Table 1. It can be seen that our protein-dependent library clearly outperforms both D10 and D02 on all the amino acids. In fact, the χ_{1} accuracy of P10 improves the higher one of D10 and D02 by at least 5% on 15 out of all the 18 amino acids, whereas the improvement is at least 10% on five amino acids. The overall χ_{1} accuracy of both P10 and P02 is above 80%, which improves the corresponding input library by about 6.5%. We also run a well-known side-chain prediction method, TreePack, proposed in [2], which is based on a global search algorithm, i.e., tree decomposition, on the same data set. The overall accuracy of TreePack is about 82%. This demonstrates that without global optimization/search, our protein-dependent rotamer library is still comparable to the global search methods.
One thing to notice is that the improvement of the accuracy of our libraries is not consistent on different amino acids. There are some amino acids whose accuracy has been improved significantly (around 15-20%). There are also few amino acids whose improvement is below average. We investigate the fact and discover that accuracy of all the amino acids with a big aromatic ring has been improved greatly. They are HIS, PHE, TRP and TYR. A possible explanation is that because of the size of the aromatic rings, the conformations of the amino acids with aromatic rings highly depend on the local geometric environments, rather than depending only on backbone information. These amino acids are more constrained in choosing a particular rotamer even if the rotamer is heavily represented within the database. Therefore, ϕ and ψ angles, which are the only information used by backbone-dependent rotamer libraries, are not enough to reveal the conformation preference of such side-chains. Therefore, the simple statistics from the generic protein databases can be misleading.
One interesting thing is that on MET, which does not have any big aromatic ring, our protein-dependent rotamer libraries still have about 10% improvement on χ_{1} and about 20% improvements on χ_{1+2} and χ_{1+2+3}. It turns out that MET is the only amino acid which has a sulfur atom inside its side chain (not the end of the side-chain). Sulfur has a bigger atomic radius with respect to carbon and nitrogen. So the conformation of sulfur dihedral angles are more constrained than the carbon or nitrogen dihedral angles, thus largely depend on the specific protein structure. However, this explanation can be questioned because of the low improvement of the accuracy for CYS, which also has a sulfur atom in its side-chain. This is due to the fact that in proteins, if suitable condition found, two CYS amino acids normally form a disulfide bond which changes its regular conformation. Such trend can already be partially captured by the statistics on the protein databases. Therefore, the protein-dependent rotamer libraries do not encode much more information than the backbone-dependent rotamer libraries. On the other hand, the energy function used in our method does not contain a specific term for disulfide bond, whereas side-chain prediction programs, which apply global search techniques, normally encode such a term. Therefore, it can be expected that our method does not improve the backbone-dependent libraries on CYS as much as the global search methods do.
It is shown in Table 1 that the overall accuracy of D10 is slightly higher than D02. Consequently, the overall accuracy of P10 is also higher than P02, which demonstrates that the improvement of our method is consistent and not input library dependent. Therefore, with an improved backbone-dependent or backbone-independent rotamer library, a better overall accuracy can be expected for our method.
Performance on rotamer ranking
To demonstrate the potential for the global optimization/search algorithms to benefit from our protein-dependent rotamer library, we further evaluate the ability to re-rank the input rotamers of our library. It has been shown in Table 1 that P10 is better than P02 and D10 is better than D02. Therefore, from now on, we will use only P10 and D10 for comparison.
Comparison of rotamer libraries for rotamer ranking
Average rank of correct rotamer | ||
---|---|---|
Dihedral angle | Rank of P10 | Rank of D10 |
χ _{1} | 1.6301 | 1.738 |
χ _{1+2} | 2.6663 | 2.9517 |
Average probability of finding correct rotamers at top 1 position | ||
Dihedral angle | Probability of P10 | Probability of D10 |
χ _{1} | 0.8018 | 0.6470 |
χ _{1+2} | 0.6111 | 0.4127 |
Average probability of finding correct rotamer at top 2 positions | ||
Dihedral angle | Probability of P10 | Probability of D10 |
χ _{1} | 0.8984 | 0.8899 |
χ _{1+2} | 0.7248 | 0.7053 |
Average probability of finding correct rotamer at top 3 positions | ||
Dihedral angle | Probability of P10 | Probability of D10 |
χ _{1} | 0.9313 | 0.9265 |
χ _{1+2} | 0.7655 | 0.7479 |
Another set of criteria which has been evaluated is whether our top choices are populated by correct rotamers or not. We calculate the average probability of finding correct rotamers in the top 1,2 and 3 choices. As shown in Table 2, if we only consider the first choice, the average probability of correct rotamers boosts up from 0.65 to 0.80 for χ_{1} and from 0.41 to 0.61 for χ_{1+2}. In the cases of top 2 and top 3 choices, even though the probability of both libraries are high, our library still outperforms the backbone-dependent library. Note that the probability here is the prior probability by the corresponding library, which is different from the accuracy of the library. Such prior probabilities are widely used in the energy functions of the global search algorithms to direct the search procedure. Therefore, with high average probability, the energy functions can be more accurate, which can thus reduce the search space of the side-chain packing methods.
Combining the results from Table 1 and Table 2, our protein-dependent rotamer library significantly increases the average accuracy for side-chain prediction, reduces the average rank of the first rotamers, and assigns higher prior probabilities to correct rotamers. All of these improvements are done without doing global optimization/search, which clearly shows the potential of the protein-dependent library to benefit the side-chain packing methods.
Comparison of inference algorithms
We finally report the comparison between different inference algorithms for MRF on our problem. We compare the performances of four approximate inference algorithms namely,
LBP Loopy belief propagation
GBP Generalized belief propagation
MF Mean field approximation
TRBP Tree re-weighted belief propagation
Comparison of inference algorithms
Comparison | ||||
---|---|---|---|---|
Attribute | LBP | GBP | MF | TRBP |
Accuracy of χ_{1} | 80.07 | 80.03 | 79.54 | 76.45 |
Accuracy of χ_{1+2} | 60.78 | 60.72 | 60.33 | 55.58 |
Average rank of χ_{1} | 1.50 | 1.51 | 1.54 | 1.59 |
Average rank of χ_{1+2} | 2.23 | 2.25 | 2.33 | 2.45 |
Average execution time (in seconds) | 29.99 | 63.19 | 14.17 | 189.94 |
Discussion
We have demonstrated that by modeling protein structures by MRF and applying inference algorithms to estimate the marginal distributions of the side-chains, we can get a much more accurate rotamer library, which we refer to as protein-dependent rotamer library. One may argue that although we do not use the global optimization/search algorithms, our method encodes the energy information. However, the energy information we used is mainly for the purpose of setting the potentials to build MRF, rather than for directing any search procedure. In this sense, the traditional backbone-dependent rotamer libraries also encode the energy information, in another form. The traditional libraries are mainly based on the statistics of the solved protein structures, which are assumed to be the global minimum conformation of the natural energy function. Therefore, doing statistics on such structures also encode energy information. This is further confirmed by the facts that if high-resolution protein structures are used to build the traditional libraries or if the core regions with high electri-density are used to do the statistics, the accuracy of the traditional libraries can be increased significantly [5]. Therefore, although our library uses energy functions in a more explicit way than the traditional libraries, it can be expected that the global search algorithms can still benefit a lot from our library. Since the source code for both SCWRL and TreePack are not publicly available, we can not directly encode our library into such global search methods. We are implementing our own dead-end-elimination, tree-decomposition and other search algorithms, such as A* search, to test the performance of combining our library with global search algorithms.
Although probabilistic graphical models are a relatively new tool for protein structure modeling, they have already proved their efficacy. However, they are not immune from all kinds of drawbacks. In our use of belief propagation, it is not guaranteed that the inference algorithm will converge. We avoid this problem by setting maximum limit on the number of iterations. Nevertheless, for our dataset loopy belief propagation is able to converge within 100 iterations for around 97% input proteins. Moreover, for those cases where LBP fails to converge, we still have moderately good results. Thus, this limitation is not as much daunting as it first seems to be. Other deterministic methods also can suffer from errant input. For example, both TreePack [2, 3] and Scwrl4 [5] use tree decomposition technique to employ exhaustive search strategy. However, there is still no guarantee that the tree width of the tree decomposition must be small. Therefore, it is also possible that for some large input proteins, such methods may also fail to produce results or find an approximate solution.
One important application of our method is side-chain prediction for flexible backbone conformations. In many applications, a large number of backbone structures are available, such as the protein structure sampling, protein structures gathered from different protein structure prediction servers, or protein backbone refinement tasks. In such cases, there are a large number of close-to-native backbone structures, but none of them is the native structure. The traditional side-chain packing methods usually take only one single backbone structure as input, which cannot be applied here, because the set of structures contain important information about the native structure. Therefore, all of these close-to-native structures should be considered simultaneously. Our method can easily take a set of flexible backbone structures as input. In this case, the backbone structures will also be modeled as random variables. The standard belief propagation algorithms can still be used to infer the marginal distributions for side-chain rotamers under the condition of flexible backbones.
Conclusion
In this paper, we have proposed a novel type of backbone-dependent rotamer library, i.e., protein-dependent rotamer library, which encodes structural information of all the spatially neighboring residues. By estimating the marginal distributions of the side-chains in a Markov random field model, the proposed library significantly boosts the accuracy of the input rotamer library, without global optimization or search. The proposed library can hopefully lead to the performance improvements of the side-chain prediction methods.
Declarations
Acknowledgements
We thank anonymous reviewers whose suggestions improved the manuscript. We are grateful to Dunbrack lab for issuing us the academic licenses of both Scwrl4 and the backbone dependent rotamer libraries. We thank Jinbo Xu to make the TreePack executable version publicly available. This work is supported by a grant from King Abdullah University of Science and Technology.
This article has been published as part of BMC Bioinformatics Volume 12 Supplement 14, 2011: 22nd International Conference on Genome Informatics: Bioinformatics. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2105/12?issue=S14.
Authors’ Affiliations
References
- Dunbrack R Jr: Rotamer libraries in the 21st century. Current Opinion in Structural Biology 2002, 12(4):431–440. 10.1016/S0959-440X(02)00344-5View ArticlePubMedGoogle Scholar
- Xu J: Rapid protein side-chain packing via tree decomposition. Current Opinion in Structural Biology 2005, 3500: 423–439.Google Scholar
- Xu J, Berger B: Fast and accurate algorithms for protein side-chain packing. Journal of the ACM 2006, 53(4):533–557. 10.1145/1162349.1162350View ArticleGoogle Scholar
- Wang Q, Canutescu A, Dunbrack R Jr: SCWRL and MolIDE: Computer programs for side-chain conformation prediction and homology modeling. Nature Protocols 2008, 3(12):1832–1847. 10.1038/nprot.2008.184PubMed CentralView ArticlePubMedGoogle Scholar
- Krivov G, Shapovalov M, Dunbrack R Jr: Improved prediction of protein side-chain conformations with SCWRL4. Proteins: Structure, Function and Bioformatics 2009, 77(4):778–795. 10.1002/prot.22488View ArticleGoogle Scholar
- Rohl C, Strauss C, Misura K, Baker D: Protein Structure Prediction Using Rosetta. Methods in Enzymology 2004, 383: 66–93.View ArticlePubMedGoogle Scholar
- Liang S, Grishin NV: Side-chain modeling with an optimized scoring function. Protein Science 2002, 11(2):322–331.PubMed CentralView ArticlePubMedGoogle Scholar
- Roitberg A, Elber R: Modeling side chains in peptides and proteins: Application of the locally enhanced sampling and the simulated annealing methods to find minimum energy conformations. The Journal of chemical physics 1991, 95(12):9277- 9287. 10.1063/1.461157View ArticleGoogle Scholar
- Street AG, Mayo SL: Intrinsic β -sheet propensities result from van der Waals interactions between side chains and the local backbone. Proceedings of the National Academy of Sciences of the United States of America 1999, 96(16):9074–9076. 10.1073/pnas.96.16.9074PubMed CentralView ArticlePubMedGoogle Scholar
- Mendes J, Nagarajaram HA, Soares CM, Blundell TL, Carrondo MA: Incorporating knowledge-based biases into an energy-based side-chain modeling method: Application to comparative modeling of protein structure. Biopolymers 2001, 59(2):72- 86. 10.1002/1097-0282(200108)59:2<72::AID-BIP1007>3.0.CO;2-SView ArticlePubMedGoogle Scholar
- Desmet J, De Maeyer M, Hazes B, Lasters I: The dead-end elimination theorem and its use in protein side-chain positioning. Nature 1992, 356(6369):539–542. 10.1038/356539a0View ArticlePubMedGoogle Scholar
- De Maeyer M, Desmet J, Lasters I: All in one: A highly detailed rotamer library improves both accuracy and speed in the modelling of sidechains by dead-end elimination. Folding and Design 1997, 2: 53–66. 10.1016/S1359-0278(97)00006-0View ArticlePubMedGoogle Scholar
- Canutescu A, Shelenkov A, Dunbrack R Jr: A graph-theory algorithm for rapid protein side-chain prediction. Protein Science 2003, 12(9):2001–2014. 10.1110/ps.03154503PubMed CentralView ArticlePubMedGoogle Scholar
- Chazelle B, Kingsford C, Singh M: A semidefinite programming approach to side chain positioning with new rounding strategies. INFORMS Journal on Computing 2004, 16(4):380–392. 10.1287/ijoc.1040.0096View ArticleGoogle Scholar
- Kingsford C, Chazelle B, Singh M: Solving and analyzing side-chain positioning problems using linear and integer programming. Bioinformatics 2005, 21(7):1028–1036. 10.1093/bioinformatics/bti144View ArticlePubMedGoogle Scholar
- Zhang J, Gao X, Xu J, Li M: Rapid and accurate protein side chain prediction with local backbone information. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) 2008, 4955 LNBI: 285–299.Google Scholar
- Holm L, Sander C: Fast and simple Monte Carlo algorithm for side chain optimization in proteins: Application to model building by homology. Proteins: Structure, Function and Genetics 1992, 14(2):213–223. 10.1002/prot.340140208View ArticleGoogle Scholar
- Vasquez M: An evaluation of discrete and continuum search techniques for conformational analysis of side chains in proteins. Biopolymers 1995, 36: 53–70. 10.1002/bip.360360106View ArticleGoogle Scholar
- Hwang J, Liao W: Side-chain prediction by neural networks and simulated annealing optimization. Protein engineering 1995, 8(4):363–370. 10.1093/protein/8.4.363View ArticlePubMedGoogle Scholar
- Lee C, Subbiah S: Prediction of protein side-chain conformation by packing optimization. Journal of Molecular Biology 1991, 217(2):373–388. 10.1016/0022-2836(91)90550-PView ArticlePubMedGoogle Scholar
- Dunbrack R Jr, Cohen F: Bayesian statistical analysis of protein side-chain rotamer preferences. Protein Science 1997, 6(8):1661–1681. 10.1002/pro.5560060807PubMed CentralView ArticlePubMedGoogle Scholar
- Dunbrack R Jr, Karplus M: Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains. Nature Structural Biology 1994, 1(5):334–340. 10.1038/nsb0594-334View ArticlePubMedGoogle Scholar
- Lovell S, Word J, Richardson J, Richardson D: The penultimate rotamer library. Proteins: Structure, Function and Genetics 2000, 40(3):389–408. 10.1002/1097-0134(20000815)40:3<389::AID-PROT50>3.0.CO;2-2View ArticleGoogle Scholar
- Shapovalov MV, Dunbrack RL Jr: A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions. Structure 2011, 19(6):844–858. 10.1016/j.str.2011.03.019PubMed CentralView ArticlePubMedGoogle Scholar
- Bhat TN, Sasisekharan V, Vijayan M: An analysis of side-chain conformation in proteins. International journal of peptide and protein research 1979, 13(2):170–184.View ArticlePubMedGoogle Scholar
- Chandrasekaran R, Ramachandran GN: Studies on the conformation of amino acids. XI. Analysis of the observed side group conformation in proteins. International journal of protein research 1970, 2(4):223–233.PubMedGoogle Scholar
- Benedetti E, Morelli G, Nmethy G, Scheraga HA: Statistical and energetic analysis of side-chain conformations in oligopeptides. International journal of peptide and protein research 1983, 22: 1–15.View ArticlePubMedGoogle Scholar
- Ponder JW, Richards FM: Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequences for different structural classes. Journal of Molecular Biology 1987, 193(4):775–791. 10.1016/0022-2836(87)90358-5View ArticlePubMedGoogle Scholar
- Kono H, Doi J: A new method for side-chain conformation prediction using a Hopfield network and reproduced rotamers. Journal of Computational Chemistry 1996, 17(14):1667–1683.View ArticleGoogle Scholar
- De Maeyer M, Desmet J, Lasters I: All in one: A highly detailed rotamer library improves both accuracy and speed in the modelling of sidechains by dead-end elimination. Folding and Design 1997, 2: 53–66. 10.1016/S1359-0278(97)00006-0View ArticlePubMedGoogle Scholar
- Janin J, Wodak S, Levitt M, Maigret B: Conformation of amino acid side chains in proteins. Journal of Molecular Biology 1978, 125(3):357–386. 10.1016/0022-2836(78)90408-4View ArticlePubMedGoogle Scholar
- McGregor MJ, Islam SA, Sternberg JE: Analysis of the relationship between slide-chain conformation and secondary structure in globular proteins. Journal of Molecular Biology 1987, 198(2):295–310. 10.1016/0022-2836(87)90314-7View ArticlePubMedGoogle Scholar
- Dunbrack RL Jr, Karplus M: Backbone-dependent rotamer library for proteins. Application to side-chain prediction. Journal of Molecular Biology 1993, 230(2):543–574. 10.1006/jmbi.1993.1170View ArticlePubMedGoogle Scholar
- Schrauber H, Eisenhaber F, Argos P: Rotamers: To be or not to be? An analysis of amino acid side-chain conformations in globular proteins. Journal of Molecular Biology 1993, 230(2):592–612. 10.1006/jmbi.1993.1172View ArticlePubMedGoogle Scholar
- Peterson R, Dutton P, Wand A: Improved side-chain prediction accuracy using an ab initio potential energy function and a very large rotamer library. Protein Science 2004, 13(3):735–751. 10.1110/ps.03250104PubMed CentralView ArticlePubMedGoogle Scholar
- Dunbrack R Jr, Karplus M: Backbone-dependent rotamer library for proteins. Application to side-chain prediction. Journal of Molecular Biology 1993, 230(2):543–574. 10.1006/jmbi.1993.1170View ArticlePubMedGoogle Scholar
- Kamisetty H, Xing EP, Langmead CJ: Free energy estimates of all-atom protein structures using generalized belief propagation. Journal of Computational Biology 2008, 15(7):755–766. 10.1089/cmb.2007.0131View ArticlePubMedGoogle Scholar
- Chu W, Ghahramani Z, Wild DL: A graphical model for protein secondary structure prediction. 2004, 161–168.Google Scholar
- Yanover C, Weiss Y: Approximate inference and protein-folding. Advances in Neural Information Processing Systems 2003, 15: 1457–1464.Google Scholar
- Yedidia JS, Freeman WT, Weiss Y: Constructing free-energy approximations and generalized belief propagation algorithms. IEEE Transactions on Information Theory 2005, 51(7):2282- 2312. 10.1109/TIT.2005.850085View ArticleGoogle Scholar
- 3D Analysis: Dangle Software for Geometry Measurements[http://pibs.duke.edu/software/dangle.php]
- Moreland JL, Gramada A, Buzko OV, Zhang Q, Bourne PE: The Molecular Biology Toolkit (MBT): A modular platform for developing molecular visualization applications. BMC Bioinformatics 2005., 6(21):Google Scholar
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