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Although not being classified as the most fundamental protein structural elements like α-helices and β-strands, the loop segment may play considerable roles for protein stability, flexibility, and dynamic activity. Meanwhile, the protein loop is also quite elusive; i.e. its interactions with the other parts of protein as well as its own shape-maintaining forces have still remained as a puzzle or at least not quite clear yet. Here, we report a molecular force, the so-called polar hydrogen-π interaction (Hp-π), which may play an important role in supporting the backbones of protein loops. By conducting the potential energy surface scanning calculations on the quasi π-plane of peptide bond unit, we have observed the following intriguing phenomena: (1) when the polar hydrogen atom of a peptide unit is perpendicularly pointing to the π-plane of other peptide bond units, a remarkable Hp-π interaction occurs; (2) the interaction is distance and orientation dependent, acting in a broad space, and belonging to the 'point-to-plane' one. The molecular force reported here may provide useful interaction concepts and insights into better understanding the loop's unique stability and flexibility feature, as well as the driving force of the protein global folding.

Due to the low toxicity, easy synthesis, rapid elimination, and less side effect, more and more peptide inhibitors are emerging as the effective drugs that are clinically used in therapies of a number of diseases. At the same time the computer-aided drug design (CADD) methods have remarkably developed. In this mini review the newly developed peptide inhibitors and drugs are introduced, including peptide vaccines for cancers, peptide inhibitors for HIV, Alzheimer's disease and related diseases, and the peptides as the leading compounds of drugs. The recent progress in the theory and methodology of peptide inhibitor design is reviewed. (1) The flexible protein-peptide docking model is introduced, in which the peptide structures are treated as segment-flexible chains using genetic algorithm and special force field parameters. (2) The "Wenxiang diagram" is illustrated for protein-peptide interaction analysis that has been successfully used in the coiled-coil interaction analysis. (3) The "Distorted key" theory is reviewed, which is an effective method to convert the peptide inhibitors to the small chemical drugs. (4) The amino acid property-based peptide prediction method (AABPP) is described that is a twolevel QSAR prediction network for the bioactivity prediction of peptide inhibitors. (5) Finally, several types of molecular interactions between protein and peptide ligands are summarized, including cation-π interactions; polar hydrogen-π interactions; and π-π stocking interactions.

In the design of peptide inhibitors the huge possible variety of the peptide sequences is of high concern. In collaboration with the fast accumulation of the peptide experimental data and database, a statistical method is suggested for peptide inhibitor design. In the two-level peptide prediction network (2L-QSAR) one level is the physicochemical properties of amino acids and the other level is the peptide sequence position. The activity contributions of amino acids are the functions of physicochemical properties and the sequence positions. In the prediction equation two weight coefficient sets {ak} and {bl} are assigned to the physicochemical properties and to the sequence positions, respectively. After the two coefficient sets are optimized based on the experimental data of known peptide inhibitors using the iterative double least square (IDLS) procedure, the coefficients are used to evaluate the bioactivities of new designed peptide inhibitors. The two-level prediction network can be applied to the peptide inhibitor design that may aim for different target proteins, or different positions of a protein. A notable advantage of the two-level statistical algorithm is that there is no need for host protein structural information. It may also provide useful insight into the amino acid properties and the roles of sequence positions.

This review is to summarize three new QSAR (quantitative structure-activity relationship) methods recently developed in our group and their applications for drug design. Based on more solid theoretical models and advanced mathematical techniques, the conventional QSAR technique has been recast in the following three aspects. (1) In the fragment-based two dimensional QSAR, or abbreviated as FB-QSAR, the molecular structures in a family of drug candidates are divided into several fragments according to the substitutes being investigated. The bioactivities of drug candidates are correlated with physicochemical properties of the molecular fragments through two sets of coefficients: one is for the physicochemical properties and the other for the molecular fragments. (2) In the multiple field three dimensional QSAR, or MF-3D-QSAR, more molecular potential fields are integrated into the comparative molecular field analysis (CoMFA) through two sets of coefficients: one is for the potential fields and the other for the Cartesian three dimensional grid points. (3) In the AABPP (amino acid-based peptide prediction), the bioactivities of peptides or proteins are correlated with the physicochemical properties of all or partial residues of the sequence through two sets of coefficients: one is for the physicochemical properties of amino acids and the other for the weight factors of the residues. Meanwhile, an iterative double least square (IDLS) technique is developed for solving the two sets of coefficients in a training dataset alternately and iteratively. Using the two sets of coefficients, one can predict the bioactivity of a query peptide, protein, or drug candidate. Compared with the old methods, the new QSAR approaches as summarized in this review possess machine learning ability, can remarkably enhance the prediction power, and provide more structural information. Meanwhile, the future challenge and possible development in this area have been briefly addressed as well.

It has tremendous values for both drug discovery and basic research to develop a solid bioinformatical tool for guiding peptide reagent design. Based on the physical and chemical properties of amino acids, a new strategy for peptide reagent design, the so-called AABPD (amino acid based-peptide design), is proposed. The peptide samples in a training dataset are described by a series of HMLP (heuristic molecular lipophilicity potential) parameters and other physicochemical properties of amino acid residues that form a three-dimensional data matrix where each component is defined by three indexes: the first index refers to the peptide samples, the second to the amino acid positions, and the third to the amino acid parameters. The binding free energy between a peptide ligand and its protein receptor is calculated by a linear free energy equation through the physicochemical parameters, resulting in a set of simultaneous linear equations between the bioactivity of the peptides and the physicochemical properties of amino acids. An iterative double least square technique is developed for the solution of the three-dimensional simultaneous linear equation set to determine the amino acid position coefficients of peptide sequence and the physicochemical parameter coefficients of amino acid residues alternately. The two sets of coefficients thus obtained are used for predicting the bioactivity of other query peptide reagents. Two calculation examples, the peptide substrate specificity of the SARS coronavirus 3C-like proteinase and the affinity prediction for epitope-peptides with Class I MHC molecules are studied by using the peptide reagent design strategy., (Copyright 2007 Wiley Periodicals, Inc.)

A new peptide design strategy, the amino acid-based peptide prediction (AABPP) approach, is applied for predicting the affinity of epitope-peptides with class I MHC molecule HLA-A*0201. The AABPP approach consists of two sets of predictive coefficients. The former is the coefficients for the physicochemical properties of amino acids and the latter is the weight factors for the residue positions in a peptide sequence. An iterative double least square technique is introduced to determine the two sets of coefficients alternately through a benchmark dataset. The coefficients converged through such an iterative process are further used to predict the bioactivities of query peptides. In the AABPP algorithm, the following eight physicochemical properties are used as the descriptors of amino acids: (i) lipophilic indices, (ii) hydrophilic indices, (iii) lipophilic surface area, (iv) hydrophilic surface area, (v) alpha-potency indices, (vi) beta-potency indices, (vii) coil-potency indices and (viii) volume of amino acid side chains. In comparison with the existing methods in this area, a remakable advantage of the current approach is that there is no need to know the exact conformation of a query peptide and its alignment with a template. The two steps are indispensable but cannot always be successfully realized otherwise. It is anticipated that the AABPP approach will become a powerful tool for peptide drug design, or at least play a complemetary role to the existing methods.