Unleashing chemical power from protein sequence space toward genetically encoded “click” chemistry

We propose the concept of genetically encoded “click” chemistry (GECC) to describe the “perfect” peptide-protein reactive partners and use SpyTag/SpyCatcher chemistry as a prototype to illustrate their structural plasticity, robust interaction, and versatile applications.     

An alignment-free measure based on physicochemical properties of amino acids for protein sequence comparison

Sequence comparison is an important topic in bioinformatics. With the exponential increase of biological sequences, the traditional protein sequence comparison methods — the alignment methods become limited, so the alignment-free methods are widely proposed in the past two decades. In this paper, we considered not only the six typical physicochemical properties of amino acids, but also their frequency and positional distribution. A 51-dimensional vector was obtained to describe the protein sequence. We got a pairwise distance matrix by computing the standardized Euclidean distance, and discriminant analysis and phylogenetic analysis can be made. The results on the Influenza A virus and ND5 datasets indicate that our method is accurate and efficient for classifying proteins and inferring the phylogeny of species.     

On a geometry-based approach to protein sequence alignment

We consider a novel numerical representation of proteins obtained by assigning to individual amino acids the polar coordinate on a unit circle. As a result one can represent protein sequence as one-dimensional numerical sequence, the entries of which when subtracted facilitates search for alignment between pairs of proteins of interest. The alignment is sought by shifting one sequence relative to another by several sequence units to the left or to the right. The novel approach is illustrated on two yeast proteins having 174 and 171 amino acids. Visiting Emeritus from the Department of Mathematics & Computer Science Drake University, Des Moines, Iowa.     

New graphical representation of a DNA sequence based on the ordered dinucleotides and its application to sequence analysis

Graphical representation of a DNA sequence is a powerful tool for basic biological research. Based on the ordered dinucleotides, we propose a novel three dimensional (3D) graphical representation without circuit or degeneracy. Simultaneously, we derive the projection curve of the 3D graph. These two curves have good visualization for longer DNA sequences. The utility of the proposed curves is illustrated by mutation analysis, similarity analysis, and evolutionary relationships of different species. The results indicate that our method is efficient and powerful. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Long range interactions on wires: a reciprocal space based formalism

There are many atomic scale systems in materials, chemistry, and biology that can be effectively modeled as finite in two of the physical spatial dimensions and periodically replicated in the third including nanoscale metallic and semiconducting wires, carbon nanotubes, and DNA. However, it is difficult to design techniques to treat long range forces in these systems without truncation or recourse to slowly convergent supercells or computationally inefficient Poisson solvers. In this paper, a rigorous reciprocal space based formalism which permits long range forces on wires to be evaluated simply and easily via a small modification of existing methods for three dimensional periodicity is derived. The formalism is applied to determine long range interactions both between point particles using an Ewald-like approach and the continuous charge distributions that appear in electronic structure calculations. In this way, both empirical force field calculations and, for example, plane-wave based density functional theory computations on wires can be performed easily. The methodology is tested on model and realistic systems including a lithium doped carbon nanotube.     

RNA-binding residues in sequence space: Conservation and interaction patterns

RNA-binding proteins (RBPs) perform fundamental and diverse functions within the cell. Approximately 15% of proteins sequences are annotated as RNA-binding, but with a significant number of proteins without functional annotation, many RBPs are yet to be identified. A percentage of uncharacterised proteins can be annotated by transferring functional information from proteins sharing significant sequence homology. However, genomes contain a significant number of orphan open reading frames (ORFs) that do not share significant sequence similarity to other ORFs, but correspond to functional proteins. Hence methods for protein function annotation that go beyond sequence homology are essential. One method of annotation is the identification of ligands that bind to proteins, through the characterisation of binding site residues. In the current work RNA-binding residues (RBRs) are characterised in terms of their evolutionary conservation and the patterns they form in sequence space. The potential for such characteristics to be used to identify RBPs from sequence is then evaluated.In the current work the conservation of residues in 261 RBPs is compared for (a) RBRs vs. non-RBRs surface residues, and for (b) specific and non-specific RBRs. The analysis shows that RBRs are more conserved than other surface residues, and RBRs hydrogen-bonded to the RNA backbone are more conserved than those making hydrogen bonds to RNA bases. This observed conservation of RBRs was then used to inform the construction of RBR sequence patterns from known protein–RNA structures. A series of RBR patterns were generated for a case study protein aspartyl-tRNA synthetase bound to tRNA; and used to differentiate between RNA-binding and non-RNA-binding protein sequences. Six sequence patterns performed with high precision values of >80% and recall values 7 times that of an homology search. When the method was expanded to the complete dataset of 261 proteins, many patterns were of poor predictive value, as they had not been manipulated on a family-specific basis. However, two patterns with precision values ≥85% were used to make function predictions for a set of hypothetical proteins. This revealed a number of potential RBPs that require experimental verification.     

Multiple sequence alignment algorithm based on a dispersion graph and ant colony algorithm

In this article, we describe a representation for the processes of multiple sequences alignment (MSA) and used it to solve the problem of MSA. By this representation, we took every possible aligning result into account by defining the representation of gap insertion, the value of heuristic information in every optional path and scoring rule. On the basis of the proposed multidimensional graph, we used the ant colony algorithm to find the better path that denotes a better aligning result. In our article, we proposed the instance of three‐dimensional graph and four‐dimensional graph and advanced a special ichnographic representation to analyze MSA. It is yet only an experimental software, and we gave an example for finding the best aligning result by three‐dimensional graph and ant colony algorithm. Experimental results show that our method can improve the solution quality on MSA benchmarks. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009     

Effect of single-point sequence alterations on the aggregation propensity of a model protein

Sequences of contemporary proteins are believed to have evolved through a process that optimized their overall fitness, including their resistance to deleterious aggregation. Biotechnological processing may expose therapeutic proteins to conditions that are much more conducive to aggregation than those encountered in a cellular environment. An important task of protein engineering is to identify alternative sequences that would protect proteins when processed at high concentrations without altering their native structure associated with specific biological function. Our computational studies exploit parallel tempering simulations of coarse-grained model proteins to demonstrate that isolated amino acid residue substitutions can result in significant changes in the aggregation resistance of the protein in a crowded environment while retaining protein structure in isolation. A thermodynamic analysis of protein clusters subject to competing processes of folding and association shows that moderate mutations can produce effects similar to those caused by changes in system conditions, including temperature, concentration, and solvent composition, that affect the aggregation propensity. The range of conditions where a protein can resist aggregation can therefore be tuned by sequence alterations, although the protein generally may retain its generic ability for aggregation.     

DNA sequence design based on template strategy

In DNA based computation and DNA nanotechnology, the design of proper DNA sequences has turned out to be an elementary problem. This paper takes a further look at the template strategy proposed in work by Frutos, A. G. et al. (Nucleic Acids Res. 1997, 25, 4748-4757). The H-measure proposed by Garzon et al. (Proceedings of the Second Annual Genetic Programming Conference, 1997; pp 472-487) is combined in this strategy to optimize the template and map sets obtained. Finally we describe a constructing method that can still produce more sequences by the results obtained in this paper.     

MSAID: multiple sequence alignment based on a measure of information discrepancy

We propose an algorithm of global multiple sequence alignment that is based on a measure of what we call information discrepancy. The algorithm follows a progressive alignment iteration strategy that makes use of what we call a function of degree of disagreement (FDOD). MSAID begins with distance calculation of pairwise sequences, based on FDOD as a numerical scoring measure. In the next step, the resulting distance matrix is used to construct a guide tree via the neighbor-joining method. The tree is then used to produce a multiple alignment. Current alignment is next used to produce a new matrix and a new tree (with FDOD scoring measure again). This iterative process continues until convergence criteria (or a stopping rule) are satisfied. MSAID was tested and compared with other prior methods by using reference alignments from BAliBASE 2.01. For the alignments with no large N/C-terminal extensions or internal insertions MSAID received the top overall average in the tests. Moreover, the results of testing indicate that MSAID performs as well as other alignment methods with an occasional tendency to perform better than these prior techniques. We, therefore, believe that MSAID is a solid and reliable method of choice, which is often (if not always) superior to other global alignment techniques.     

Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold

A series of 2,4-disubstituted pyridine derivatives has been designed, synthesised and evaluated as thrombin inhibitors. A Grignard exchange reaction was used to introduce various benzoyl substituents in position 4 of the pyridine ring, where they serve as P3 residues in binding to thrombin. In position 2 of the pyridine ring, a para-amidinobenzylamine moiety was incorporated as P1 residue by an SNAr reaction using ammonia as nucleophile followed by a reductive amination. A crystal structure obtained for one of the compounds in the active site of thrombin revealed that the basic amidine group of the inhibitor was anchored to Asp 189 at the bottom of the S1 pocket. A comparison with melagatran, bound in the active site of thrombin, revealed a good shape match but lack of hydrogen bonding possibilities in the S2-S3 region for the thrombin inhibitors reported in this study.     

Synthesis and biological properties of a tryptophan-containing fragment of a myelin protein and its analogs

1. By the azide condensation of fragments followed by the hydrogenolysis of the completely protected nonapeptides formed, the encephalitogenic nonapeptides with the structure Phe-Ser-Try-Gly-Ala-Glu-Gly-Gln-Arc and two of its analogs — the 6-glycine and 5,6-diglycine compounds, have been synthesized. 2. It has been shown that the 6-glycine analog induces EAE, i.e., the side chain in position 6 is not essential for the appearance of EAE activity.     

Synthesis and biological properties of a tryptophan-containing fragment of a myelin protein and its analogs

Summary 1. By the azide condensation of fragments followed by the hydrogenolysis of the completely protected nonapeptides formed, the encephalitogenic nonapeptides with the structure Phe-Ser-Try-Gly-Ala-Glu-Gly-Gln-Arc and two of its analogs — the 6-glycine and 5,6-diglycine compounds, have been synthesized.2. It has been shown that the 6-glycine analog induces EAE, i.e., the side chain in position 6 is not essential for the appearance of EAE activity.3. The absence of an encephalitogenic effect in the 5,6-diglycine analog permits the conclusion that the side chain of the alanine-5 makes a contribution to the induction of the disease.4. The N-acetyl derivative of the encephalitogenic nonapeptide retains a high EAE activity.Institute of Molecular Biology and Genetics, Academy of Sciences of the Ukrainian SSR, Kiev. A. V. Palladin Institute of Biochemistry, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 507–517, July–August, 1976.     

Chemical and biological sensors based on organic thin-film transistors

The application of organic thin-film transistors (OTFTs) to chemical and biological sensing is reviewed. This review covers transistors that are based on the modulation of current through thin organic semiconducting films, and includes both field-effect and electrochemical transistors. The advantages of using OTFTs as sensors (including high sensitivity and selectivity) are described, and results are presented for sensing analytes in both gaseous and aqueous environments. The primary emphasis is on the major developments in the field of OTFT sensing over the last 5–10 years, but some earlier work is discussed briefly to provide a foundation.