Knowledge-based Potential Functions Research Articles

FFENCODER-PL: Pair Wise Energy Descriptors for Protein-Ligand Pose Selection.

Scoring functions are the essential component in molecular docking methods. An accurate scoring function is expected to distinguish the native ligand pose from decoy poses. Our previous experience (Pei et al. J. Chem. Inf. Model. 2019, 59 (7), 3305-3315) proved that combining the random forest (RF) algorithm with knowledge-based potential functions can emphasize germane pair wise interactions and improve the performance of original knowledge-based potential functions on protein-ligand decoy detection. One of the most important potential function classes is the force field (FF) potential with one example being the Amber collection of FFs, which are widely available in the AMBER suite of simulation programs. However, for use in RF modeling studies, one needs pair wise energies that are hard to directly extract from Amber. To address this issue, FFENCODER-PL was constructed to calculate the pair wise energies based on the FF14SB and GAFF2 FFs in Amber. FFENCODER-PL was validated using 275 ligand and 21 protein-ligand structures. RF models were built by combining an RF classification algorithm with the pair wise energies calculated from FFENCODER-PL. CASF-2016 (Su et al. J. Chem. Inf. Model. 2019, 59, 895-913) was employed to test the performance of the resultant RF models, which outperformed 33 scoring functions on accuracy and native ranking tests. For the best decoy RMSD test, RF models give a best decoy with an RMSD of around 2 Å from the native pose after including the best decoy-decoy comparisons in the RF model. The relative importance of the RF algorithm and force field potentials was also tested with the results suggesting that both the RF algorithm and force field potentials are important and combining them is the only way to achieve high accuracy. Finally, FFENCODER-PL makes force field-based pair wise energies available for further development of machine learning-based scoring functions. The codes and data used in this paper can be found at https://github.com/JunPei000/Amber_protein_ligand_encoding.

Identification of native protein structures captured by principal interactions

BackgroundEvaluation of protein structure is based on trustworthy potential function. The total potential of a protein structure is approximated as the summation of all pair-wise interaction potentials. Knowledge-based potentials (KBP) are one type of potential functions derived by known experimentally determined protein structures. Although several KBP functions with different methods have been introduced, the key interactions that capture the total potential have not studied yet.ResultsIn this study, we seek the interaction types that preserve as much of the total potential as possible. We employ a procedure based on the principal component analysis (PCA) to extract the significant and key interactions in native protein structures. We call these interactions as principal interactions and show that the results of the model that considers only these interactions are very close to the full interaction model that considers all interactions in protein fold recognition. In fact, the principal interactions maintain the discriminative power of the full interaction model. This method was evaluated on 3 KBPs with different contact definitions and thresholds of distance and revealed that their corresponding principal interactions are very similar and have a lot in common. Additionally, the principal interactions consisted of 20 % of the full interactions on average, and they are between residues, which are considered important in protein folding.ConclusionsThis work shows that all interaction types are not equally important in discrimination of native structure. The results of the reduced model based on principal interactions that were very close to the full interaction model suggest that a new strategy is needed to capture the role of remaining interactions (non-principal interactions) to improve the power of knowledge-based potential functions.

Discrimination power of knowledge-based potential dictated by the dominant energies in native protein structures.

Extracting a well-designed energy function is important for protein structure evaluation. Knowledge-based potential functions are one type of the energy functions which can be obtained from known protein structures. The pairwise potential between atom types is approximated using Boltzmann's law which relates the frequency of atom types to its potential. The total energy is approximated as a summation of pairwise potential between the atomic pairs. In the present study, the performance of knowledge-based potential function was assessed based on the strength of interaction between groups of amino acids. The dominant energies involved in the pairwise potentials were revealed by eigenvalue analysis of the matrix, the elements of which represent the energy between amino acids. For this purpose, the matrix including the mean of the energies of residue-residue interaction types was constructed using 500 native protein structures. The matrix has a dominant eigenvalue and amino acids, with LEU, VAL, ILE, PHE, TYR, ALA and TRP having high values along the dominant eigenvector. The results show that the ranking of amino acids is consistent with the power of amino acids in discriminating native structures using K-alphabet reduced model. In the reduced interactions, only amino acids from a subset of all 20 amino acids, along with their interactions are considered to assess the energy. In the K-alphabet reduced model, the reduced structures are constructed based on only the K-amino acid types. The dominant K-alphabet reduced model derived for the k-first amino acids in the list [LEU, VAL, PHE, ILE, TYR, ALA, TRP] of amino acids has the best discrimination of native structure among all possible K-alphabet reduced models. Knowledge-based potentials might be improved with a new strategy.

Hydrophobic residues can identify native protein structures.

Evaluation of protein structures needs a trustworthy potential function. Although several knowledge-based potential functions exist, the impact of different types of amino acids in the scoring functions has not been studied yet. Previously, we have reported the importance of nonlocal interactions in scoring function (based on Delaunay tessellation) in discrimination of native structures. Then, we have questioned the structural impact of hydrophobic amino acids in protein fold recognition. Therefore, a Hydrophobic Reduced Model (HRM) was designed to reduce protein structure of FS (Full Structure) into RS (Reduced Structure). RS is considered as a reduced structure of only seven hydrophobic amino acids (L, V, F, I, A, W, Y) and all their interactions. The presented model was evaluated via four different performance metrics including the number of correctly identified natives, the Z-score of the native energy, the RMSD of the minimum score, and the Pearson correlation coefficient between the energy and the model quality. Results indicated that only nonlocal interactions between hydrophobic amino acids could be sufficient and accurate enough for protein fold recognition. Interestingly, the results of HRM is significantly close to the model that considers all amino acids (20-amino acid model) to discriminate the native structure of the proteins on eleven decoy sets. This indicates that the power of knowledge-based potential functions in protein fold recognition is mostly due to hydrophobic interactions. Hence, we suggest combining a different well-designed scoring function for non-hydrophobic interactions with HRM to achieve better performance in fold recognition.

Free Energy Perturbation Calculations of the Thermodynamics of Protein Side-Chain Mutations

Protein side-chain mutation is fundamental both to natural evolutionary processes and to the engineering of protein therapeutics, which constitute an increasing fraction of important medications. Molecular simulation enables the prediction of the effects of mutation on properties such as binding affinity, secondary and tertiary structure, conformational dynamics, and thermal stability. A number of widely differing approaches have been applied to these predictions, including sequence-based algorithms, knowledge-based potential functions, and all-atom molecular mechanics calculations. Free energy perturbation theory, employing all-atom and explicit-solvent molecular dynamics simulations, is a rigorous physics-based approach for calculating thermodynamic effects of, for example, protein side-chain mutations. Over the past several years, we have initiated an investigation of the ability of our most recent free energy perturbation methodology to model the thermodynamics of protein mutation for two specific problems: protein–protein binding affinities and protein thermal stability. We highlight recent advances in the field and outline current and future challenges.

BCL::MP-fold: Membrane protein structure prediction guided by EPR restraints.

For many membrane proteins, the determination of their topology remains a challenge for methods like X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. Electron paramagnetic resonance (EPR) spectroscopy has evolved as an alternative technique to study structure and dynamics of membrane proteins. The present study demonstrates the feasibility of membrane protein topology determination using limited EPR distance and accessibility measurements. The BCL::MP-Fold (BioChemical Library membrane protein fold) algorithm assembles secondary structure elements (SSEs) in the membrane using a Monte Carlo Metropolis (MCM) approach. Sampled models are evaluated using knowledge-based potential functions and agreement with the EPR data and a knowledge-based energy function. Twenty-nine membrane proteins of up to 696 residues are used to test the algorithm. The RMSD100 value of the most accurate model is better than 8 Å for 27, better than 6 Å for 22, and better than 4 Å for 15 of the 29 proteins, demonstrating the algorithms' ability to sample the native topology. The average enrichment could be improved from 1.3 to 2.5, showing the improved discrimination power by using EPR data.

Docking polysaccharide to proteins that have a Tryptophan box in the binding pocket

Protein–carbohydrate interactions (PCIs) involve a variety of essential biological processes such as cell recognition and migration, metabolism processes and immunological reactions, which are important for securing functions of living organisms. Due to the polysaccharide structural diversity and dynamics flexibility, PCIs can be very difficult for experimental measurement and computer prediction. Here we report a simple method for docking polysaccharide to proteins whose binding pockets have a Tryptophan box. The method samples polysaccharide conformations using constraint conditions imposed by the box, evaluate the conformation energies based on a knowledge-based potential function, and finds the best docking structures using the conventional Monte Carlo simulated annealing technique. We applied the method to dock polysaccharides with 2 to 4 monomers to three carbohydrate-binding proteins, whose pockets have clear aromatic residue-defined binding channels. The predictions found correct carbohydrate binding conformations with atomic RMSD of 1.1–1.6 Å from X-ray crystal structures. The calculation can be performed in ordinary PC and only cost a couple of minutes for a single docking. Our method, when combined with other docking programs, provides a reliable start conformation for further accurate simulation of PCIs.

PiDNA: predicting protein–DNA interactions with structural models

Predicting binding sites of a transcription factor in the genome is an important, but challenging, issue in studying gene regulation. In the past decade, a large number of protein–DNA co-crystallized structures available in the Protein Data Bank have facilitated the understanding of interacting mechanisms between transcription factors and their binding sites. Recent studies have shown that both physics-based and knowledge-based potential functions can be applied to protein–DNA complex structures to deliver position weight matrices (PWMs) that are consistent with the experimental data. To further use the available structural models, the proposed Web server, PiDNA, aims at first constructing reliable PWMs by applying an atomic-level knowledge-based scoring function on numerous in silico mutated complex structures, and then using the PWM constructed by the structure models with small energy changes to predict the interaction between proteins and DNA sequences. With PiDNA, the users can easily predict the relative preference of all the DNA sequences with limited mutations from the native sequence co-crystallized in the model in a single run. More predictions on sequences with unlimited mutations can be realized by additional requests or file uploading. Three types of information can be downloaded after prediction: (i) the ranked list of mutated sequences, (ii) the PWM constructed by the favourable mutated structures, and (iii) any mutated protein–DNA complex structure models specified by the user. This study first shows that the constructed PWMs are similar to the annotated PWMs collected from databases or literature. Second, the prediction accuracy of PiDNA in detecting relatively high-specificity sites is evaluated by comparing the ranked lists against in vitro experiments from protein-binding microarrays. Finally, PiDNA is shown to be able to select the experimentally validated binding sites from 10 000 random sites with high accuracy. With PiDNA, the users can design biological experiments based on the predicted sequence specificity and/or request mutated structure models for further protein design. As well, it is expected that PiDNA can be incorporated with chromatin immunoprecipitation data to refine large-scale inference of in vivo protein–DNA interactions. PiDNA is available at: http://dna.bime.ntu.edu.tw/pidna.

Z-score biological significance of binding hot spots of protein interfaces by using crystal packing as the reference state

Characterization of binding hot spots of protein interfaces is a fundamental study in molecular biology. Many computational methods have been proposed to identify binding hot spots. However, there are few studies to assess the biological significance of binding hot spots. We introduce the notion of biological significance of a contact residue for capturing the probability of the residue occurring in or contributing to protein binding interfaces. We take a statistical Z-score approach to the assessment of the biological significance. The method has three main steps. First, the potential score of a residue is defined by using a knowledge-based potential function with relative accessible surface area calculations. A null distribution of this potential score is then generated from artifact crystal packing contacts. Finally, the Z-score significance of a contact residue with a specific potential score is determined according to this null distribution. We hypothesize that residues at binding hot spots have big absolute values of Z-score as they contribute greatly to binding free energy. Thus, we propose to use Z-score to predict whether a contact residue is a hot spot residue. Comparison with previously reported methods on two benchmark datasets shows that this Z-score method is mostly superior to earlier methods. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction.

DBD2BS: connecting a DNA-binding protein with its binding sites.

By binding to short and highly conserved DNA sequences in genomes, DNA-binding proteins initiate, enhance or repress biological processes. Accurately identifying such binding sites, often represented by position weight matrices (PWMs), is an important step in understanding the control mechanisms of cells. When given coordinates of a DNA-binding domain (DBD) bound with DNA, a potential function can be used to estimate the change of binding affinity after base substitutions, where the changes can be summarized as a PWM. This technique provides an effective alternative when the chromatin immunoprecipitation data are unavailable for PWM inference. To facilitate the procedure of predicting PWMs based on protein–DNA complexes or even structures of the unbound state, the web server, DBD2BS, is presented in this study. The DBD2BS uses an atom-level knowledge-based potential function to predict PWMs characterizing the sequences to which the query DBD structure can bind. For unbound queries, a list of 1066 DBD–DNA complexes (including 1813 protein chains) is compiled for use as templates for synthesizing bound structures. The DBD2BS provides users with an easy-to-use interface for visualizing the PWMs predicted based on different templates and the spatial relationships of the query protein, the DBDs and the DNAs. The DBD2BS is the first attempt to predict PWMs of DBDs from unbound structures rather than from bound ones. This approach increases the number of existing protein structures that can be exploited when analyzing protein–DNA interactions. In a recent study, the authors showed that the kernel adopted by the DBD2BS can generate PWMs consistent with those obtained from the experimental data. The use of DBD2BS to predict PWMs can be incorporated with sequence-based methods to discover binding sites in genome-wide studies.Available at: http://dbd2bs.csie.ntu.edu.tw/, http://dbd2bs.csbb.ntu.edu.tw/, and http://dbd2bs.ee.ncku.edu.tw.

Structure and Age Jointly Influence Rates of Protein Evolution

What factors determine a protein's rate of evolution are actively debated. Especially unclear is the relative role of intrinsic factors of present-day proteins versus historical factors such as protein age. Here we study the interplay of structural properties and evolutionary age, as determinants of protein evolutionary rate. We use a large set of one-to-one orthologs between human and mouse proteins, with mapped PDB structures. We report that previously observed structural correlations also hold within each age group – including relationships between solvent accessibility, designabililty, and evolutionary rates. However, age also plays a crucial role: age modulates the relationship between solvent accessibility and rate. Additionally, younger proteins, despite being less designable, tend to evolve faster than older proteins. We show that previously reported relationships between age and rate cannot be explained by structural biases among age groups. Finally, we introduce a knowledge-based potential function to study the stability of proteins through large-scale computation. We find that older proteins are more stable for their native structure, and more robust to mutations, than younger ones. Our results underscore that several determinants, both intrinsic and historical, can interact to determine rates of protein evolution.

Predicting Target DNA Sequences of DNA-Binding Proteins Based on Unbound Structures

DNA-binding proteins such as transcription factors use DNA-binding domains (DBDs) to bind to specific sequences in the genome to initiate many important biological functions. Accurate prediction of such target sequences, often represented by position weight matrices (PWMs), is an important step to understand many biological processes. Recent studies have shown that knowledge-based potential functions can be applied on protein-DNA co-crystallized structures to generate PWMs that are considerably consistent with experimental data. However, this success has not been extended to DNA-binding proteins lacking co-crystallized structures. This study aims at investigating the possibility of predicting the DNA sequences bound by DNA-binding proteins from the proteins' unbound structures (structures of the unbound state). Given an unbound query protein and a template complex, the proposed method first employs structure alignment to generate synthetic protein-DNA complexes for the query protein. Once a complex is available, an atomic-level knowledge-based potential function is employed to predict PWMs characterizing the sequences to which the query protein can bind. The evaluation of the proposed method is based on seven DNA-binding proteins, which have structures of both DNA-bound and unbound forms for prediction as well as annotated PWMs for validation. Since this work is the first attempt to predict target sequences of DNA-binding proteins from their unbound structures, three types of structural variations that presumably influence the prediction accuracy were examined and discussed. Based on the analyses conducted in this study, the conformational change of proteins upon binding DNA was shown to be the key factor. This study sheds light on the challenge of predicting the target DNA sequences of a protein lacking co-crystallized structures, which encourages more efforts on the structure alignment-based approaches in addition to docking- and homology modeling-based approaches for generating synthetic complexes.

On the analysis of protein–protein interactions via knowledge‐based potentials for the prediction of protein–protein docking

Development of effective methods to screen binary interactions obtained by rigid-body protein-protein docking is key for structure prediction of complexes and for elucidating physicochemical principles of protein-protein binding. We have derived empirical knowledge-based potential functions for selecting rigid-body docking poses. These potentials include the energetic component that provides the residues with a particular secondary structure and surface accessibility. These scoring functions have been tested on a state-of-art benchmark dataset and on a decoy dataset of permanent interactions. Our results were compared with a residue-pair potential scoring function (RPScore) and an atomic-detailed scoring function (Zrank). We have combined knowledge-based potentials to score protein-protein poses of decoys of complexes classified either as transient or as permanent protein-protein interactions. Being defined from residue-pair statistical potentials and not requiring of an atomic level description, our method surpassed Zrank for scoring rigid-docking decoys where the unbound partners of an interaction have to endure conformational changes upon binding. However, when only moderate conformational changes are required (in rigid docking) or when the right conformational changes are ensured (in flexible docking), Zrank is the most successful scoring function. Finally, our study suggests that the physicochemical properties necessary for the binding are allocated on the proteins previous to its binding and with independence of the partner. This information is encoded at the residue level and could be easily incorporated in the initial grid scoring for Fast Fourier Transform rigid-body docking methods.

A novel side-chain orientation dependent potential derived from random-walk reference state for protein fold selection and structure prediction.

BackgroundAn accurate potential function is essential to attack protein folding and structure prediction problems. The key to developing efficient knowledge-based potential functions is to design reference states that can appropriately counteract generic interactions. The reference states of many knowledge-based distance-dependent atomic potential functions were derived from non-interacting particles such as ideal gas, however, which ignored the inherent sequence connectivity and entropic elasticity of proteins.MethodologyWe developed a new pair-wise distance-dependent, atomic statistical potential function (RW), using an ideal random-walk chain as reference state, which was optimized on CASP models and then benchmarked on nine structural decoy sets. Second, we incorporated a new side-chain orientation-dependent energy term into RW (RWplus) and found that the side-chain packing orientation specificity can further improve the decoy recognition ability of the statistical potential.SignificanceRW and RWplus demonstrate a significantly better ability than the best performing pair-wise distance-dependent atomic potential functions in both native and near-native model selections. It has higher energy-RMSD and energy-TM-score correlations compared with other potentials of the same type in real-life structure assembly decoys. When benchmarked with a comprehensive list of publicly available potentials, RW and RWplus shows comparable performance to the state-of-the-art scoring functions, including those combining terms from multiple resources. These data demonstrate the usefulness of random-walk chain as reference states which correctly account for sequence connectivity and entropic elasticity of proteins. It shows potential usefulness in structure recognition and protein folding simulations. The RW and RWplus potentials, as well as the newly generated I-TASSER decoys, are freely available in http://zhanglab.ccmb.med.umich.edu/RW.

Computation of conformational transitions in proteins by virtual atom molecular mechanics as validated in application to adenylate kinase

Many proteins function through conformational transitions between structurally disparate states, and there is a need to explore transition pathways between experimentally accessible states by computation. The sizes of systems of interest and the scale of conformational changes are often beyond the scope of full atomic models, but appropriate coarse-grained approaches can capture significant features. We have designed a comprehensive knowledge-based potential function based on a C alpha representation for proteins that we call the virtual atom molecular mechanics (VAMM) force field. Here, we describe an algorithm for using the VAMM potential to describe conformational transitions, and we validate this algorithm in application to a transition between open and closed states of adenylate kinase (ADK). The VAMM algorithm computes normal modes for each state and iteratively moves each structure toward the other through a series of intermediates. The move from each side at each step is taken along that normal mode showing greatest engagement with the other state. The process continues to convergence of terminal intermediates to within a defined limit--here, a root-mean-square deviation of 1 A. Validations show that the VAMM algorithm is highly effective, and the transition pathways examined for ADK are compatible with other structural and biophysical information. We expect that the VAMM algorithm can address many biological systems.

Free‐energy function based on an all‐atom model for proteins

We have developed a free-energy function based on an all-atom model for proteins. It comprises two components, the hydration entropy (HE) and the total dehydration penalty (TDP). Upon a transition to a more compact structure, the number of accessible configurations arising from the translational displacement of water molecules in the system increases, leading to a water-entropy gain. To fully account for this effect, the HE is calculated using a statistical-mechanical theory applied to a molecular model for water. The TDP corresponds to the sum of the hydration energy and the protein intramolecular energy when a fully extended structure, which possesses the maximum number of hydrogen bonds with water molecules and no intramolecular hydrogen bonds, is chosen as the standard one. When a donor and an acceptor (e.g., N and O, respectively) are buried in the interior after the break of hydrogen bonds with water molecules, if they form an intramolecular hydrogen bond, no penalty is imposed. When a donor or an acceptor is buried with no intramolecular hydrogen bond formed, an energetic penalty is imposed. We examine all the donors and acceptors for backbone-backbone, backbone-side chain, and side chain-side chain intramolecular hydrogen bonds and calculate the TDP. Our free-energy function has been tested for three different decoy sets. It is better than any other physics-based or knowledge-based potential function in terms of the accuracy in discriminating the native fold from misfolded decoys and the achievement of high Z-scores.

Explicit Orientation Dependence in Empirical Potentials and Its Significance to Side-Chain Modeling

Protein structure modeling and prediction have important applications throughout the biological sciences, from the design of pharmaceuticals to the elucidation of enzyme mechanisms. At the core of most protein modeling is an energy function, the minimum of which represents the free energy "cost" for forming a correct protein structure. The most commonly used energy functions are knowledge-based statistical potential functions; that is, they are empirically derived from statistical analysis of a set of high-resolution protein structures. When that kind of potential function is constructed, the anisotropic orientation dependence between the interacting groups is a critical component for accurately representing key molecular interactions, such as those involved in protein side-chain packing. In the literature, however, many potential functions are limited in their ability to describe orientation dependence. In all-atom potentials, they typically ignore heterogeneous chemical-bond connectivity. In coarse-grained potentials, such as (semi)-residue-based potentials, the simplified representation of residues often reduces the sensitivity of the potential to side-chain orientation. Recently, in an effort to maximally capture the orientation dependence in side-chain interactions, a new type of all-atom statistical potential was developed: OPUS-PSP (potential derived from side-chain packing). The key feature of this potential is its explicit description of orientation dependence in molecular interactions, which is achieved with a basis set of 19 rigid-body blocks extracted from the chemical structures of 20 amino acid residues. This basis set is specifically designed to maximally capture the essential elements of orientation dependence in molecular packing interactions. The potential is constructed from the orientation-specific packing statistics of pairs of those blocks in a nonredundant structural database. On decoy set tests, OPUS-PSP significantly outperforms most of the existing knowledge-based potentials in terms of both its ability to recognize native structures and its consistency in achieving high Z scores across decoy sets. The application of OPUS-PSP to conformational modeling of side chains has led to another method, called OPUS-Rota. In terms of combined speed and accuracy, OPUS-Rota outperforms all of the other methods in modeling side-chain conformation. In this Account, we briefly outline the basic scheme of the OPUS-PSP potential and its application to side-chain modeling via OPUS-Rota. Future perspectives on the modeling of orientation dependence are also discussed. The computer programs for OPUS-PSP and OPUS-Rota can be downloaded at http://sigler.bioch.bcm.tmc.edu/MaLab . They are free for academic users.

Solvent dramatically affects protein structure refinement

One of the most challenging problems in protein structure prediction is improvement of homology models (structures within 1-3 A C(alpha) rmsd of the native structure), also known as the protein structure refinement problem. It has been shown that improvement could be achieved using in vacuo energy minimization with molecular mechanics and statistically derived continuously differentiable hybrid knowledge-based (KB) potential functions. Globular proteins, however, fold and function in aqueous solution in vivo and in vitro. In this work, we study the role of solvent in protein structure refinement. Molecular dynamics in explicit solvent and energy minimization in both explicit and implicit solvent were performed on a set of 75 native proteins to test the various energy potentials. A more stringent test for refinement was performed on 729 near-native decoys for each native protein. We use a powerfully convergent energy minimization method to show that implicit solvent (GBSA) provides greater improvement for some proteins than the KB potential: 24 of 75 proteins showing an average improvement of >20% in C(alpha) rmsd from the native structure with GBSA, compared to just 7 proteins with KB. Molecular dynamics in explicit solvent moved the structures further away from their native conformation than the initial, unrefined decoys. Implicit solvent gives rise to a deep, smooth potential energy attractor basin that pulls toward the native structure.

A knowledge-based structure-discriminating function that requires only main-chain atom coordinates

BackgroundThe use of knowledge-based potential function is a powerful method for protein structure evaluation. A variety of formulations that evaluate single or multiple structural features of proteins have been developed and studied. The performance of functions is often evaluated by discrimination ability using decoy structures of target proteins. A function that can evaluate coarse-grained structures is advantageous from many aspects, such as relatively easy generation and manipulation of model structures; however, the reduction of structural representation is often accompanied by degradation of the structure discrimination performance.ResultsWe developed a knowledge-based pseudo-energy calculating function for protein structure discrimination. The function (Discriminating Function using Main-chain Atom Coordinates, DFMAC) consists of six pseudo-energy calculation components that deal with different structural features. Only the main-chain atom coordinates of N, Cα, and C atoms for the respective amino acid residues are required as input data for structure evaluation. The 231 target structures in 12 different types of decoy sets were separated into 154 and 77 targets, and function training and the subsequent performance test were performed using the respective target sets. Fifty-nine (76.6%) native and 68 (88.3%) near-native (< 2.0 Å Cα RMSD) targets in the test set were successfully identified. The average Cα RMSD of the test set resulted in 1.174 with the tuned parameters. The major part of the discrimination performance was supported by the orientation-dependent component.ConclusionDespite the reduced representation of input structures, DFMAC showed considerable structure discrimination ability. The function can be applied to the identification of near-native structures in structure prediction experiments.

OPUS‐Ca: A knowledge‐based potential function requiring only Cα positions

In this paper, we report a knowledge-based potential function, named the OPUS-Ca potential, that requires only Calpha positions as input. The contributions from other atomic positions were established from pseudo-positions artificially built from a Calpha trace for auxiliary purposes. The potential function is formed based on seven major representative molecular interactions in proteins: distance-dependent pairwise energy with orientational preference, hydrogen bonding energy, short-range energy, packing energy, tri-peptide packing energy, three-body energy, and solvation energy. From the testing of decoy recognition on a number of commonly used decoy sets, it is shown that the new potential function outperforms all known Calpha-based potentials and most other coarse-grained ones that require more information than Calpha positions. We hope that this potential function adds a new tool for protein structural modeling.