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Biomedical subjects

K C Chou

Publications and source records attributed to K C Chou.

At least 91 records · Page 5Linked to original sources
PubMed1993

Studies on the specificity of HIV protease: an application of Markov chain theory.

A sequence-coupled (Markov chain) model is proposed to predict the cleavage sites in proteins by proteases with extended specificity subsites. In addition to the probability of an amino acid occurring at each of these subsites as observed from a training set of oligopeptides known cleavable by HIV protease, the conditional probabilities as reflected by the neighbor-coupled effect along the subsite sequence are also taken into account. These conditional probabilities are derived from an expanded training set consisting of sufficiently large peptide sequences generated by the Monte Carlo sampling process. Very high accuracy was obtained in predicting protein cleavage sites by both HIV-1 and HIV-2 proteases. The new method provides a rapid and accurate means for analyzing the specificity of HIV protease, and hence can be used to help find effective inhibitors of HIV protease as potential drugs against AIDS. The principle of this method can also be used to study the specificity of any multisubsite enzyme.

Acquired Immunodeficiency Syndrome↗
PubMed1993

A new approach to predicting protein folding types.

A new method is proposed for predicting the folding type of a protein according to its amino acid composition based on the following physical picture: (1) a protein is characterized as a vector of 20-dimensional space, in which its 20 components are defined by the compositions of its 20 amino acids; and (2) the similarity of two proteins is proportional to the mutual projection of their characterized vectors, and hence inversely proportional to the size of their correlation angle. Thus, the prediction is performed by calculating the correlation angles of the vector for the predicted protein with a set of standard vectors representing the norms of four protein folding types (i.e., all alpha, all beta, alpha + beta, and alpha/beta). In comparison with the existing methods, the new method has the merits of yielding a higher rate of correct prediction, displaying a more intuitive physical picture, and being convenient in application. For instance, in predicting the 64 proteins in the development set based on which the standard vectors are derived, the average accuracy rate is 83.6%, which is higher than that obtained for the same set of proteins by any of the existing methods. The average accuracy predicted for an independent set of 35 proteins of known X-ray structure is 91.4%, which is significantly higher than any of the reported accuracies so far, implying that the new method is of great value in practical application. All of these have demonstrated that the new method as proposed in this paper is characterized by an improved feature in both self-consistency and extrapolating-effectiveness.

Amino Acids↗
PubMed1993

Graphic analysis of codon usage strategy in 1490 human proteins.

The frequencies of bases A (adenine), C (cytosine), G (guanine), and T (thymine) occurring in codon position i, denoted by ai, ci, gi, and ti, respectively (i = 1,2,3), have been calculated and diagrammatized for the 1490 human proteins in the codon usage table for primate genes compiled recently. Based on the characteristic graphs thus obtained, an overall picture of codon base distribution has been provided, and the relevant biological implication discussed. For the first codon position, it is shown in most cases that G is the most dominant base, and that the relationship g1 > a1 > c1 > t1 generally holds true. For the second codon position, A is generally the most dominant base and G is the one with the least occurrence frequently, with the relationship of a2 > t2 > c2 > g2. As to the third codon position, the values of g3 + c3 vary from 0.27 to 1, roughly keeping the relationship of c3 > g3 > a3 = t3 for the majority of cases. Interestingly, if the average frequencies for bases A, C, G, and T are defined as a = (a1 + a2 + a3)/3, c = (c1 + c2 + c3)/3, g = (g1 + g2 + g3)/3, and t = (t1 + t2 + t3)/3, respectively, we find that a2 + c2 + g2 + t2 < 1/3 is valid almost without exception. Such a characteristic inequality might reflect some inherent rule of codon usage, although its biological implications is unclear.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗
PubMed1993

Conformational change during photocycle of bacteriorhodopsin and its proton-pumping mechanism.

Based on the recent finding on the structural difference of seven helix bundles in the all-trans and 13-cis bacteriorhodopsins, the distances among the key groups performing the function of proton translocation as well as their microenvironments have been investigated. Consequently, a pore-gated model was proposed for the light-driven proton-pumping mechanism of bacteriorhodopsin. According to this model, the five double-bounded polyene chain in retinal chromophore can be phenomenologically likened to a molecular "lever," whose one end links to a "piston" (the beta-ionone ring) and the other end to a pump "relay station" (the Schiff base). During the photocycle of bacteriorhodopsin, the molecular "lever" is moving up and down as marked by the position change of the "piston," so as to trigger the gate of pore to open and close alternately. When the "piston" is up, the pore-controlled gate is open so that the water channel from Asp-96 to the Schiff base and that from the Schiff base to Asp-85 is established; when the "piston" is down, the pore-controlled gate is closed and the water channels for proton transportation in both the cytoplasmic half and extracellular half are blocked. The current model allows a consistent interpretation of a great deal of experimental data and also provides a useful basis for further investigating the mechanism of proton pumping by bacteriorhodopsin.

Amino Acid Sequence↗
PubMed1992

Role of loop-helix interactions in stabilizing four-helix bundle proteins.

One of the critical issues regarding proteins with a four-helix bundle motif is which interactions play the major role in stabilizing this type of folded structure: the interaction among the four alpha-helices or the interaction between the loop and helix segments. To answer this question, an energetic analysis has been carried out for three proteins with a four-helix bundle--namely, methemerythrin, cytochrome b-562, and cytochrome c'. The structures on which the analysis has been made were derived from their respective crystallographic coordinates. All three proteins have long helices (16-26 residues) and most of their loops are short (3-5 residues). However, it was found in all three proteins that loop-helix interactions were stronger than helix-helix interactions. Moreover, not only the nonbonded component but also the electrostatic component of the interaction energy were dominated by loop-helix interactions rather than by interhelix interactions, although the latter involve favorable helix-dipole interactions due to the antiparallel arrangement of neighboring helices. The results of the energetic analysis indicate that the loop segments, whether they are in a theoretical model or in real proteins, play a significant role in stabilizing proteins with four-helix bundles.

Cytochrome b Group↗
PubMed1992

A correlation-coefficient method to predicting protein-structural classes from amino acid compositions.

A protein is usually classified into one of the following four structural classes: all alpha, all beta, (alpha + beta) and alpha/beta. In this paper, based on the maximum correlation-coefficient principle, a new formulation is proposed for predicting the structural class of a protein according to its amino acid composition. Calculations have been made for a development set of proteins from which the amino acid compositions for the standard structural classes were derived, and an independent set of proteins which are outside the development set. The former can test the self consistency of a method and the latter can test its extrapolating effectiveness. In both cases, the results showed that the new method gave a considerably higher rate of correct prediction than any of the previous methods, implying that a significant improvement has been achieved by implementing the maximum-correlation-coefficient principle in the new method.

Algorithms↗
PubMed1992

Energy-optimized structure of antifreeze protein and its binding mechanism.

A combination of Monte Carlo simulated annealing and energy minimization was utilized to determine the conformation of the antifreeze protein from the fish winter flounder. It was found from the energy-optimized structure that the hydroxyl groups of its four threonine residues, i.e. Thr2, Thr13, Thr24, Thr35, are aligned on almost the same line parallel to the helix axis and separated successively by 16.1, 16.0 and 16.2 A, respectively, very close to the 16.6 A repeat spacing along [0112] in ice. Based on such a space match, a zipper-like model is proposed to elucidate the binding mechanism of the antifreeze protein to ice crystals. According to the current model, the antifreeze protein may bind to an ice nucleation structure in a zipper-like fashion through hydrogen bonding of the hydroxyl groups of these four Thr residues to the oxygen atoms along the [0112] direction in ice lattice, subsequently stopping or retarding the growth of ice pyramidal planes so as to depress the freeze point. The calculated results and the binding mechanism thus derived accord with recent experimental observations. The mechanistic implications derived from such a special antifreeze molecule might be generally applied to elucidate the structure-function relationship of other antifreeze proteins with the following two common features: (1) recurrence of a Thr residue (or any other polar amino acid residue whose side-chain can form a hydrogen bond with water) in an 11-amino-acid period along the sequence concerned; and (2) a high percentage of Ala residue component therein. Further experiments are suggested to test the ice binding model.

Amino Acid Sequence↗
PubMed1992

An optimization approach to predicting protein structural class from amino acid composition.

Proteins are generally classified into four structural classes: all-alpha proteins, all-beta proteins, alpha + beta proteins, and alpha/beta proteins. In this article, a protein is expressed as a vector of 20-dimensional space, in which its 20 components are defined by the composition of its 20 amino acids. Based on this, a new method, the so-called maximum component coefficient method, is proposed for predicting the structural class of a protein according to its amino acid composition. In comparison with the existing methods, the new method yields a higher general accuracy of prediction. Especially for the all-alpha proteins, the rate of correct prediction obtained by the new method is much higher than that by any of the existing methods. For instance, for the 19 all-alpha proteins investigated previously by P.Y. Chou, the rate of correct prediction by means of his method was 84.2%, but the correct rate when predicted with the new method would be 100%! Furthermore, the new method is characterized by an explicable physical picture. This is reflected by the process in which the vector representing a protein to be predicted is decomposed into four component vectors, each of which corresponds to one of the norms of the four protein structural classes.

Amino Acids↗
PubMed1992

An energy-based approach to packing the 7-helix bundle of bacteriorhodopsin.

Based on the heavy-atom coordinates determined by the electron microscopy for the seven main helical regions of bacteriorhodopsin with the all-trans retinal isomer, energy optimizations were carried out for helix bundles containing the all-trans retinal and 13-cis retinal chromophores, respectively. A combination of simulated annealing and energy minimization was utilized during the process of energy optimization. It was found that the 7-helix bundle containing the all-trans isomer is about 10 kcal/mol lower in conformational energy than that containing the 13-cis isomer. An energetic analysis indicates that such a difference in energy is consistent with the observation that absorption of a 570-nm proton is required for the conversion of a bacteriorhodopsin from its all-trans to 13-cis form. It was also found that the above conversion process is accompanied by a significant conformational perturbation around the chromophore, as reflected by the fact that the beta-ionone ring of retinal moves about 5.6 A along the direction perpendicular to the membrane plane. This is consistent with the observation by Fodor et al. (Fodor, S.P.A., Ames, J.B., Gebhard, R., van der Berg, E.M.M., Stoeckenius, W., Lugtenburg, J., & Mathies, R.A., 1988, Biochemistry 27, 7097-7101). Furthermore, it is interesting to observe that although the retinal chromophore undergoes a significant change in its spatial position, the orientation of its transition dipole changes only slightly, in accord with experimental observations. In other words, even though orientation of the retinal transition dipole is very restricted, there is sufficient room, and degrees of freedom, for the retinal chromophore to readjust its position considerably. This finding provides new insight into the subtle change of the retinal microenvironment, which may be important for revealing the proton-pumping mechanism of bacteriorhodopsin. The importance of electrostatic and nonbonded interactions in stabilizing the 7-helix bundle structure has also been analyzed. Electrostatic interactions favor an antiparallel arrangement among adjacent helices. Nonbonded interactions, however, drive most of the closely packed helices into an arrangement in which the packing angles lie around -160 degrees, a value very near the -154 degrees value computed earlier as the most favorable packing arrangement of two poly(Ala) alpha-helices (Chou, K.-C., Némethy, G., & Scheraga, H.A., 1983, J. Phys. Chem. 87, 2869-2881). The structural features of the 7-helix bundle and their relationship to those found in typical 4-helix bundle proteins are also discussed.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1992

Strong electrostatic loop-helix interactions in bundle motif protein structures.

Based on CHARMM potential (Brooks et al., 1983) an energetic analysis has been carried out for four typical 4-alpha-helix bundle proteins, i.e., methemerythrin, cytochrome b-562, cytochrome c', and bovine somatotropin. The bovine somatotropin possesses long loops, but all the other three proteins have short loops. It was found that in all these four 4-alpha-helix bundle motif structures the interaction between loops and helices was much stronger than the interaction among the four helices themselves. Particularly for the electrostatic interaction energy, the loop-helix interaction is overwhelmingly stronger than the interhelix interaction although the latter involves the favorable helix dipole interaction due to the antiparallel arrangement of neighboring alpha-helices. The present study indicates that such a conclusion holds true regardless of what loops, long or short, are in the 4-alpha-helix bundle protein, and also regardless of which empirical potential, ECEPP or CHARMM, is used for calculations although in CHARMM the electrostatic energy is much more heavily emphasized than in ECEPP. Therefore, no appropriate conclusion can be drawn in arguing whether the dipole interaction among the four alpha-helices play a stabilizing role or destabilizing role for a 4-alpha-helix bundle protein without taking into consideration the effect of interaction between helices and loops. The calculated results reported here provide, from a different point of view, insights that might be useful for revealing the essence of the driving forces during the folding of proteins.

Animals↗
PubMed1992

Monte Carlo simulation studies on the prediction of protein folding types from amino acid composition.

In the methodology development for statistical prediction of protein structures, the founders of different methods usually selected different sets of proteins to test their predicted results. Therefore, it is hard to make a fair comparison according to the results they reported. Even if the predictions by different methods are performed for the same set of proteins, there is still such a problem: a method better that the other for one set of proteins would not necessarily remain so when applied to another set of proteins. To tackle this problem, a Monte Carlo simulation method is proposed to establish an objective criterion to measure the accuracy of prediction for the protein folding type. Such an objective accuracy is actually corresponding to the asymptotical limit genereated during the Monte Carlo simulation process. Based on that, it has been found that the average objective accuracy for predicting the all-alpha, all-beta, alpha + beta, and alpha/beta proteins by the least Euclid's distance method (Nakashima, H., K. Nishikawa, and T. Ooi. 1986. J. Biochem. 99:152-162) is 73.0% and that by the least Minkowski's distance method (Chou, P.Y. 1989. Prediction in Protein Structure and the Principles of Protein Conformation. Plenum Press. New York. 549-586) is 70.9%, indicating that the former is better than the latter. However, according to the original reports, the latter claimed a rate of correct prediction with 79.7% but the former with only 70.2%, leading to a completely opposite conclusion. This indicates the necessity of establishing an objective criterion, and a comparison is meaningful only when it is based on the objective criterion. The simulation method and the idea developed here also can be applied to examine any other statistical prediction methods.

Amino Acids↗
PubMed1992

Diagrammatization of codon usage in 339 human immunodeficiency virus proteins and its biological implication.

The occurrence frequencies of bases A (adenine), C (cytosine, G (guanine), and T (thymine) occurring in the 1st, 2nd, and 3rd codon positions in the codon usage table of viral genes for the 339 human immunodeficiency virus (HIV) proteins compiled recently have been calculated and diagrammatized. For comparison, the corresponding diagrammatic representations for the 2681 human proteins from the codon usage table for primate genes are also presented. The analyzed results based on these characteristic diagrams indicate that considerably similar features have been found between HIV and human proteins for the 1st and 2nd codon positions; i.e., they are all occupied predominantly by purine, especially base A. However, a significant difference in the 3rd codon position between HIV and human proteins has been observed; i.e., human proteins are of high C + G content and low A + G content in the 3rd codon position, whereas the case is just the opposite for HIV proteins. The biological implication of such a duality on the codon bias of HIV against human proteins is discussed. It is suggested that the 1st and 2nd codon positions can be termed as the structure-determining position, and the 3rd codon position termed as the species-determining position. The diagrammatic representation and analysis method described here possess a great potential for the study of molecular evolution from the viewpoint of the genetic code for which data have been accumulated rapidly and will continue to grow at a much faster pace.

Base Composition↗
PubMed1991

A heuristic approach to predicting the tertiary structure of bovine somatotropin.

A combination of a heuristic approach and energy minimization was used to predict the three-dimensional structure of bovine somatotropin (bSt), also known as bovine growth hormone, a protein of 191 amino acids. The starting points for energy minimizations were generated from the following two types of inputs: (a) the amino acid sequence and (b) the heuristic inputs, which were derived according to physical, chemical, and biological principles by piecing together all useful information available. The predicted 3-D structure of the bSt molecule has all the features observed in four-helix bundle proteins. The four alpha-helices in bSt are intimately packed to form an assembly with an approximately square cross section. All the adjacent alpha-helices are antiparallel, with a somewhat tilted angle between each of the adjacent pairs so that the assembly of the four helices looks like a left-handed twisted bundle. There are two disulfide bonds in the bSt structure: one "hooking" the middle of a long loop with helix 4 so as to pull the long loop onto the surface of the helix bundle and the other "hooking" the C-terminal segment with the same helix so as to force the C-terminal segment to bend toward the helix bundle. As a consequence, a considerable part of the surface of the four-helix bundle is closely packed or intimately embraced by the loop segments. The predicted bSt structure has a hydrophobic core and a hydrophilic exterior surface. The energetic analysis of the predicted bSt structure indicates that the interaction between helices and loops plays a dominant role in stabilizing the four-helix bundle structure from the viewpoint of both electrostatic and nonbonded interactions. A technique called FOLD was meanwhile developed, by which one can fold a polypeptide chain into any shape as desired. This tool proved to be very useful during the heuristic model-building process.

Algorithms↗
PubMed1991

Mass-weighted molecular dynamics simulation of cyclic polypeptides.

A modified molecular dynamics (MD) method in which atomic masses are weighted was developed previously for studying the conformational flexibility of neuroregulating tetrapeptide Phe-Met-Arg-Phe-amide (FMRF-amide). The method has now been applied to longer and constrained molecules, namely a disulfide-linked cyclic hexapeptide, c[CYFQNC], and its linear and "pseudo-cyclic" analogues. The sampling of dehedral conformational space of teh linear hexapeptide in mass-weighted MD simulations was found to be improved significantly over conventional MD simulations, as in the case of the shorter FMRF-amide molecule studied previously. In the cyclic hexapeptide, the internal constraint of the molecule due to the intramolecular disulfide bond (hence the absence of free terminals in the molecule) does not adversely affect the significant improvement of conformational sampling in mass-weighted MD simulations over normal MD simulations. The pseudo-cyclic polypeptide is identical to the linear CYFQNC molecule in amino acid sequence (i.e., side chains of the cysteine residues are reduced), but the positions of its two terminal heavy atoms were held fixed in space such that the molecule has a nearly cyclic conformation. For this molecule, the mass-weighted MD simulation generated a wide range of polypeptide backbone conformations covering the internal dihedral degrees of freedom; moreover, the physical space of the pseudo-cyclic structure was also sampled in a complete revolution of the entire molecular fragment about the two fixed termini during the simulation. These characteristics suggest that mass-weighted MD can also be an extremely useful method for conformational analyses of constrained molecules and, in particular, for modeling loops on protein surfaces.

Amino Acid Sequence↗
PubMed1991

Energetic approach to the folding of alpha/beta barrels.

The folding of a polypeptide into a parallel (alpha/beta)8 barrel (which is also called a circularly permuted beta 8 alpha 8 barrel) has been investigated in terms of energy minimization. According to the arrangement of hydrogen bonds between two neighboring beta-strands of the central barrel therein, such an alpha/beta barrel structure can be folded into six different types: (1) left-tilted, left-handed crossover; (2) left-tilted, right-handed crossover; (3) nontilted, left-handed crossover; (4) nontilted, right-handed crossover; (5) right-tilted, left-handed crossover; and (6) right-tilted, right-handed crossover. Here "tilt" refers to the orientational relation of the beta-strands to the axis of the central beta-barrel, and "crossover" to the beta alpha beta folding connection feature of the parallel beta-barrel. It has been found that the right-tilted, right-handed crossover alpha/beta barrel possesses much lower energy than the other five types of alpha/beta barrels, elucidating why the observed alpha/beta barrels in proteins always assume the form of right tilt and right-handed crossover connection. As observed, the beta-strands in the energy-minimized right-tilted, right-handed crossover (alpha/beta)8-barrel are of strong right-handed twist. The value of root-mean-square fits also indicates that the central barrel contained in the lowest energy (alpha/beta)8 structure thus found coincides very well with the observed 8-stranded parallel beta-barrel in triose phosphate isomerase (TIM). Furthermore, an energetic analysis has been made demonstrating why the right-tilt, right-handed crossover barrel is the most stable structure. Our calculations and analysis support the principle that it is possible to account for the main features of frequently occurring folding patterns in proteins by means of conformational energy calculations even for very complicated structures such as (alpha/beta)8 barrels.

Hydrogen Bonding↗
PubMed1991

Simulated annealing approach to the study of protein structures.

One of the most difficult problems in predicting the three dimensional structure of proteins is how to deal with the local minimum problem. In many cases of practical interest this problem has been reduced to how to select an appropriate set of starting conformations for carrying out energy minimizations. How these starting conformations are selected, however, is often based on the physical intuition of the person doing the calculations, and hence it is hard to avoid bearing some sort of arbitrariness. To improve such a situation, we introduced the simulated annealing Monte Carlo algorithm to locate the optimal starting conformations for energy minimizations. The method developed here is valid for both single and multiple polypeptide chain systems. The annealing process can be conducted with respect to either the internal dihedral angles of a polypeptide chain or the external rotations and translations of various constituent polypeptide chains, and hence is particularly useful for studying the packing arrangements of secondary structures in proteins, such as helix/helix packing, helix/sheet packing and sheet/sheet packing. It was shown via a number of comparative calculations that the final structures obtained through the annealing process not only had lower energies than the corresponding energy-minimized structures reported previously, but also assumed the forms closer to the observations in proteins. All these results indicate that a better result can be obtained in search of low-energy structures of proteins by incorporating the simulated annealing approach.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1991

Geometric and energy parameters in lysine-retinal chromophores.

The parameters used in the computer program ECEPP (Empirical Conformational Energy Program for Peptides) have been expanded to cover some key elements in retinal-containing proteins. These elements are 'all-trans retinal lysine with unprotonated imine', 'all-trans retinal lysine with protonated imine', '13-cis retinal lysine with unprotonated imine' and '13-cis retinal lysine with protonated imine' respectively. The geometric parameters of these four new 'amino acid residues' were derived by optimizing their molecular structures with the AM1 Hamiltonian included in MOPAC (Molecular Orbital PACkage), and their partial atomic charges were determined with a CNDO/2 (Complete Neglect of Differential Overlap) calculation. The parameters for nonbonded interactions and torsional potentials were obtained from the existing ECEPP parameters through a logical extension. The augmented ECEPP system thus obtained can be employed to investigate the conformation of bacteriorhodopsin and its proton-pumping mechanism from an energetic point of view. The computer modeling study on bacteriorhodopsin and other seven-helix membrane proteins, e.g. serotonin receptor and dopamine receptor, is under way in the Upjohn Laboratories.

Bacteriorhodopsins↗