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Biomedical subjects

P K Ponnuswamy

Publications and source records attributed to P K Ponnuswamy.

At least 19 recordsLinked to original sources
PubMed2004

Stability of DNA duplexes with Watson-Crick base pairs: a predicted model.

The conformational stability (difference between the free energies of the folded and unfolded states, DeltaG degrees ) of a DNA duplex is considered as a function of component energy terms, hydrophobic, base stacking, hydrogen bonding, van der Waals, and electrostatic, and a trinucleotide-level helix stiffness parameter measured in terms of its Young's modulus. Hydrophobic and base stacking energy components were determined with the use of the crystal structure data of 30 DNA duplexes judicially selected within a resolution of 1.5 A, and hydrogen bonding, van der Waals and electrostatic terms were determined through an extensive review of experimental and theoretical studies. The stiffness indices for the trinucleotides were the ones realized by M. M. Gromiha [(2000) J. Biol. Phys. 26, 43-50] using the crystal structure data of 70 DNA duplexes. The unfolded state was treated in the classical way to determine its stability. Thermodynamically determined DeltaG degrees values for 111 DNA duplexes, with the number of base pairs ranging from 4 to 16, were selected in two sets, and the regression equation formed with one set was used to predict the stabilities of the other set, taking the energy components and the stiffness parameter to be independent variables. The computed energy terms indicate that the base stacking and hydrogen bonding forces are the dominant and the hydrophobic and electrostatic forces the weak partners in imparting stability to the duplexes. This model predicts DeltaG degrees values for DNA duplexes examined with a level of accuracy similar to that used for predictions made by the widely used nearest-neighbor models. The uniqueness of this model is that it combines the crystal and thermodynamic data for interpretation of conformational stability.

Base Pairing↗
PubMed2000

On the thermal unfolding character of globular proteins.

A theoretical model is presented to study the stepwise thermal unfolding of globular proteins using the stabilizing/destabilizing characters of amino acid residues in protein crystals. A multiple regression relation connecting the melting temperature and the amounts of stabilizing and destabilizing groups of residues in a protein, when used for the thermal behavior of peptide segments, provides reliable results on the stepwise unfolding nature of the protein. In ribonuclease A, the shell residues 16-22 are predicted to unfold earlier in the temperature range 30-45 degrees C; the beta-sheet structures undergo thermal denaturation as a single cooperative unit and there is evidence indicating the segment 106-118 as a nucleation site. In ribonuclease S, the S-peptide unfolds earlier than S-protein. The predicted average and the range of melting temperatures, and the folding pathways of a set of globular proteins, agree very well with the experimental results. The results obtained in the present study indicate that (i) most of the nucleation parts possess high relative thermal stability, (ii) the unfolded state retains some residual structure, and (iii) some segments undergo gradual and overlapping thermal denaturation.

Calorimetry, Differential Scanning↗
PubMed1997

Identification of membrane spanning beta strands in bacterial porins.

The membrane assembly of outer membrane proteins is more complex than that of transmembrane helical proteins owing to the intervention of many charged and polar residues in the membrane. Accordingly, the predictive accuracy of transmembrane beta strands is considerably lower than that of transmembrane alpha helices. In this paper we develop a set of conformational parameters for membrane spanning beta strands. We formulate an algorithm to predict the transmembrane beta strands in the family of bacterial porins based on the conformational parameters and surrounding hydrophobicities of amino acid residues. A Fortran program has been developed which takes the amino acid sequence as the input file and gives the predicted transmembrane beta strand as output. The present method predicts at an accuracy level of 82% for all the bacterial porins considered.

Amino Acid Sequence↗
PubMed1996

Internal packing conditions and fluctuations of amino acid residues in globular proteins.

In order to investigate the environmental conditions of amino acid residues in protein molecules, four kinds of packing studies (atomic, geometric, hydrophobic and hydration) were formulated and tested on two proteins; bovine pancreatic trypsin inhibitor (BPTI) and bovine pancreatic ribonuclease S (RNase S). The inter-relationship of these packings on the fluctuations of amino acid residues was analysed by comparing the packing results with the dynamical studies, such as the root-mean-square-deviation values of atomic displacements obtained from the trajectories of molecular dynamics simulation, temperature factor information from crystal structures and residue fluctuations in proteins from continuum model. These analyses yield information about the most fluctuating and most stabilizing residue sites. Comparison of the results obtained by these methods indicate a good agreement, specifying an inverse correlation between the residue packing and fluctuations. This kind of study is helpful in identifying the specific residue sites such as nucleation, receptor binding and antigenic determining sites which in a way indirectly correlates with the functional residues in protein molecules.

Amino Acids↗
PubMed1996

Hydrophobic distribution and spatial arrangement of amino acid residues in membrane proteins.

The analysis of known three-dimensional structures of membrane proteins provides an opportunity to understand their structure and stability. In this article we analyse the hydrophobic variation of amino acid residues at various ranges in membrane and aqueous parts of membrane proteins. The numerical indices for several properties of amino acid residues in membrane proteins, such as surrounding hydrophobicity, gain in surrounding hydrophobicity, hydrophobic gain ratio, accessible surface area, preference of amino acid residues in the interior and surface parts, solvent accessible reduction ratio and buriedness, were set up. The relative preference of amino acid residues at various positions of membrane proteins were obtained in a very realistic approach.

Amino Acids↗
PubMed1995

Prediction of protein secondary structures from their hydrophobic characteristics.

Deciphering the native conformation of proteins from their amino acid sequences is one of the greatest challenges in the field of molecular biology. The successful prediction of structural class may help to improve the accuracy levels of structure (secondary and tertiary) predictive schemes in globular proteins. In our earlier works we developed a new surrounding hydrophobicity scale for the 20 amino acid residues applicable for both globular and membrane proteins and used it successfully to predict the transmembrane helical and strand segments in membrane proteins. In this article we propose (i) rules to predict the structural class of proteins and (ii) a new predictive scheme for forecasting secondary structures of globular proteins, with the use of the new hydrophobicity scale. This scheme predicts the structural class and secondary structures of globular proteins to 92 and 82% levels of accuracy, respectively, far better than the levels from other existing methods.

Algorithms↗
PubMed1994

On the conformational stability of oligonucleotide duplexes and tRNA molecules.

Thermodynamic experiments provide a wealth of data about the conformational stability, viz., the free energy difference (delta G) between folded and unfolded states of DNA/RNA duplexes. However, there is no acceptable view about how the various non-covalent forces contribute individually to the observed stability. In particular, the role of the hydrophobic force is not clearly known. In this paper we quantitatively enumerate the stability factors, hydrogen bonding, base stacking, van der Waals, electrostatic, and hydrophobic interactions from the knowledge of the crystal structures of 15 DNA/RNA duplexes and two tRNA molecules, and translate them into free energy contributions to the stability of nucleic acid systems. Taking the experimental delta G values and computed component free energy terms for a set of duplexes, we set up multiple regression equations to predict their stabilities. After back-check and validity tests, we apply this model to predict delta G values for a large number of duplexes and two tRNA molecules (tRNAphe and tRNAasp). There is excellent agreement between the theoretical predictions and experimental observations. The considered duplexes with four to 16 base-pairs and the tRNA molecules have delta G values in a narrow range, 5-20 kcal mol-1, a range seen in a variety of globular proteins. There is no relationship between delta G and N, the number of nucleotides in the molecule. Base-stacking, hydrogen bonding and van der Waals factors contribute significantly, whereas hydrophobic and electrostatic factors contribute, respectively, marginally and minimally. The major factor which gives sequence specificity is base-stacking. The new set of atomic solvation parameters (ASPs) derived to estimate hydrophobic free energy brings to light the dangers of using already available ASPs, which emphasize the role of the hydrophobic factor unrealistically.

Base Sequence↗
PubMed1993

Prediction of transmembrane beta-strands from hydrophobic characteristics of proteins.

The assembly of outer-membrane proteins consisting of beta-strands as transmembrane segments is somewhat more complex when compared to the assembly of inner membrane proteins having alpha-helices as transmembrane parts. This is probably due to the difference in the amino acid sequences of the transmembrane part strands and helices. Because of this feature, most predictive schemes which are successful in predicting transmembrane helical segments fail to predict transmembrane strand segments. Here we propose a new predictive scheme for forecasting the transmembrane strand segments in outer-membrane proteins with the use of the general surrounding hydrophobicity scale developed both for the globular and membrane proteins in the preceding article. Two major features of the scheme are (i) that it does not solely depend on the amphipathic character of a sequence segment while identifying it as a transmembrane strand, and it is capable of predicting strands in varied lengths, a facility to reflect the variation in the membrane surfaces. This scheme predicts the transmembrane beta-strands in porin from R. capsulatus at 76% accuracy (giving due weights to over- and under-predictions when compared to X-ray results). The predicted beta-structure contents in OmpA, porin from E. coli and maltoporin compared with the Raman spectroscopic results at 95% level. These accuracy levels are far superior than the levels obtained from other existing methods. Apart from the above four proteins for which experimental informations are available, ten other outer-membrane proteins, for which there is no information about their secondary structure, are considered in the forecast. The results are analysed and the common features in the folds of the set of fourteen outer-membrane proteins are deduced.

Amino Acid Sequence↗
PubMed1993

Prediction of transmembrane helices from hydrophobic characteristics of proteins.

Membrane proteins, requiring to be embedded into the lipid bilayers, have evolved to have amino acid sequences that will fold with a hydrophobic surface in contact with the alkane chains of the lipids and polar surface in contact with the aqueous phases on both sides of the membrane and the polar head groups of the lipids. It is generally assumed that the characteristics of the aqueous parts of the membrane proteins are similar to those of normal globular proteins, and the embedded parts are highly hydrophobic. In our earlier works, we introduced the concept of 'surrounding hydrophobicity' and developed a hydrophobicity scale for the 20 amino acid residues, and applied it successfully to the study of the family of globular proteins. In this work we use the concept of surrounding hydrophobicity to indicate quantitatively how the aqueous parts of membrane proteins compare with the normal globular proteins, and how rich the embedded parts are in their hydrophobic activity. We then develop a surrounding hydrophobicity scale applicable to membrane proteins, by mixing judicially the surrounding hydrophobicities observed in the crystals of the membrane protein, photosynthetic reaction center from the bacterium Rhodopseudomonas viridis, porin from Rhodobacter capsulatus and a set of 64 globular proteins. A predictive scheme based on this scale predicts from amino acid sequence, transmembrane segments in PRC and randomly selected 26 membrane proteins to 80% level of accuracy. This is a much higher predictive power when compared to the existing popular methods. A new procedure to measure the amphipathicity of sequence segments is proposed, and it is used to characterize the transmembrane parts of the sample membrane proteins.

Chemical Phenomena↗
PubMed1992

Structural similarities in the repeat sequences of plasma apolipoproteins, A-I, A-IV, and E.

The presence of 22-residue repeats, each with a preferential potential to form an amphipathic alpha-helix, is a unique feature of the plasma apolipoproteins. There are 27 such repeats in the three human apolipoproteins A-I, A-IV, and E. The extent of similarities and differences among these repeats have been estimated by computing correlation coefficients, Dayhoff scores, secondary structure difference profiles, and discrete Fourier transforms. The results reveal that there is a high level of similarity among the repeats of apo A-IV, and a low level of similarity in the repeats of apo E. Within each protein, similarity among some specified repeat pairs is distinctively higher than the others. A high order of similarity is also found among certain segments of each protein with those in the other two. The repeats prefer a mostly alpha-helical structure that is amphipathic in nature. Among the repeats of the three proteins, those of apo E show a high level of divergence among themselves. A consensus alignment of the residues of the 27 repeats into a hydrophobic versus hydrophilic pattern brings to focus the possible specific structure-stabilizing factors, such as the leucine zipper and the salt bridge. The recently reported crystal structures of the human apolipoprotein E and locust apolipophorin-III support many of the predictions made in this study.

Amino Acid Sequence↗
PubMed1991

The influence of side chain structures on the residue-residue associations in globular proteins.

The relationship between the physical make-up of the side chain structure of an amino acid and its capacity to associate with other side chains in the crystalline state of protein molecules has been investigated by a linear regression study. Relevant inter- and intra-molecular forces and steric factors are taken to represent the side chain structure, while the observed atom-atom interactions in a set of protein crystals are taken to represent the residue-residue association potentials. Correlation equations are set up in such a way that, (i) the dependence of the association potential of a residue on the side chain structures of associating residues, and (ii) the dependence of the association potential of a residue on its own side chain structure are brought out separately. The results show definite quantitative relationships in each of the above two views. Particularly, the behaviour of the charged residues is highly correlated to the structural make of their side chains. It is demonstrated how and to what extent the effects of associating/preferring residues are taken care of when they associate with a certain kind of residue in the protein environment.

Amino Acids↗
PubMed1990

Variation of amino acid properties in protein secondary structures, alpha-helices and beta-strands.

A study was made on the physical, chemical, energetic, conformational, geometric, and dynamic property potentials of amino acid residues in protein secondary structures: alpha-helix and beta-strand. Property patterns were obtained by computing the average property values for specified residue units partitioned longitudinally and transversely about the chain. It was found that in alpha-helices with not more than 15 residues, there exist longitudinally opposing portions, one characteristically higher in average property potentials than the other. The helical chain, in general, acquires either an increasing or decreasing average potential in the N-terminal to C-terminal direction. The sequence-wise and surface-wise variations of property potentials in the elements of beta-structure also revealed such general patterns. Possible wrong predictions in statistical methods of one secondary structural class over the other are pointed out.

Amino Acids↗
PubMed1989

Conformational characteristics of mixed sugar puckered deoxydinucleoside triphosphate units d-pCpGp and d-pGpCp from energy minimization studies.

The deoxydinucleoside triphosphate units d-pCpGp and d-pGpCp were subjected to a rigorous theoretical investigation with a view to describing their distinctive conformational characteristics. For each unit 216 probable three-dimensional forms defined by the backbone-base dihedral angles and sugar pucker modes were considered for conformational energy minimization process and scrutinized with reference to properties, such as base-stacking, hydrogen-bonding, internal flexibility and base sequence-phosphate influence. The P-O bond torsions and the phosphate groups were treated with special attention. The results reveal a number of preferred conformational states other than the known helical forms, such as, A-, B-, C-, Z-, and Watson-Crick conformation. Many interesting one-step (change in only one of the dihedral angles or sugar puckers) conformational transitions which involve just about a kcal/mol of energy came to light. The two base sequences CG and GC were noted to differ strikingly in many of their conformational characteristics.

DNA↗
PubMed1989

Conformational characteristics of mixed sugar puckered deoxytetranucleoside triphosphate d-GpCpGpC from energy minimization studies.

As a continuation of our theoretical studies on nucleic acid subunit systems, in this article we consider the case of the tetranucleoside d-GpCpGpC, the minimally ideal representative unit for analyzing the relative stabilities of different forms of homo- and mixed helical conformation of polynucleotides. The four sugar rings are kept so as to generate B-genus, B+A genus and Z-genus conformations. Twenty five helical conformational states which resulted from judicious mixing of A-, B-, C-, W-, and Z-, states locally are subjected to energy minimization permitting the 19 dihedral angles to vary simultaneously. Conformational states corresponding to regular helical forms and mixed helical forms, when analyzed provide valuable information as to the local conformational flexibility and transitions available to polynucleotides.

DNA↗
PubMed1984

Prediction of packing of secondary structure.

An improved method of picking up candidates for predicting the packing arrangement of beta-strands and alpha-helices of the alpha/beta type domains is described here. The method of judging whether the region of the protein would fold into the alpha/beta type or not is also described. The folding constraints of globular proteins are analysed and presented in this article for application to the prediction of packing of secondary structure. The analysis of the residue-fluctuations is also applicable for the purpose.

Arabinose↗
PubMed1984

Differential equation model to study dynamic behaviour of globular proteins.

By regarding the globular proteins as spheroidal shaped bodies of uniform density, a differential equation model to study their low amplitude fluctuations was developed. It was then applied to the crystal structures of pancreatic trypsin inhibitor and ferrocytochrome c. The results were tested by comparing them with those of the dynamic simulation and temperature factor studies on the same proteins.

Animals↗