M. N. Ponnuswamy

Structural class prediction: an application of residue distribution along the sequence

Deciphering the native conformation of proteins from their amino acid sequences is one of the most challenging problems in molecular biology. Information on the secondary structure of a protein can be helpful in understanding its native folded state. In our earlier work on molecular chaperones, we have analyzed the hydrophobic and charged patches, short-, medium- and long-range contacts and residue distributions along the sequence. In this article, we have made an attempt to predict the structural class of globular and chaperone proteins based on the information obtained from residue distributions. This method predicts the structural class with an accuracy of 93 and 96%, respectively, for the four- and three-state models in a training set of 120 globular proteins, and 90 and 96%, respectively, for a test set of 80 proteins. We have used this information and methodology to predict the structural classes of chaperones. Interestingly most of the chaperone proteins are predicted under alpha/beta or mixed folding type.

Analysis of hydrophobic and charged patches and influence of medium- and long-range interactions in molecular chaperones

The amino acid composition of the aromatic residues Phe, Tyr and Trp are much less significant in chaperones and the residues Cys, Glu, His, Met and Pro vary significantly in chaperones compared to normal globular proteins. In the present work, we have analysed the hydrophobic and charged patches in molecular chaperones which provide more insight for a better understanding of chaperone folding. Also, we have investigated the role of medium- and long-range contacts in chaperones and the preference of amino acid residues influenced by these interactions. Furthermore, the role of hydrophobic and helix-forming residues and disulfide bonding in these interactions have been discussed.

Crystal Structures of two Triazole Derivatives

3-Phenyl-4-amino-5-mercapto-1,2,4-triazole(PAMT), C 8 H 8 N 4 S, F.W.=192.24, triclinic, P 1¯, a=6.1698(3)Å, b=7.1765(1)Å, c=9.9894(3)Å, f =81.87(1), g =84.97(2), n =78.81(2), V=428.72(3)Å 3 , Z=2, D cal =1.489 Mgm m 3 , w =0.330 mm m 1 , F 000 =200, u (MoK f )=0.71073 Å, final R1 and wR2 are 0.0871 and 0.2170, respectively. 3-(4-Methylphenyl)-4-amino-5-mercapto-1,2,4-triazole (MAMT), C 9 H 10 N 4 S,F.W.=206.27, triclinic, P 1 , a=5.996(1)Å, b=7.582(2)Å, c=11.143(1)Å, f =73.16(1), g =89.65(2), n =87.88(1), V=484.52(3)Å 3 , Z=2, D cal =1.414 Mgm m 3 , w =2.674 mm m 1 , F 000 =216, u (CuK f )=1.5418 Å, final R1 and wR2 are 0.0656 and 0.1820, respectively. In both of the molecules the triazole rings are planar and oriented at angles of 5.7(1) and 1.4(2) with the respective phenyl rings in MAMT and PAMT. The molecules in the unit cell are stabilized by N-H…N type hydrogen bonds in addition to van der Waals forces.

Distribution of amino acid residues and residue-residue contacts in molecular chaperones.

The amino acid distribution and residue-residue contacts in molecular chaperones are different when compared to normal globular proteins. The study of molecular chaperones reveals a different surrounding environment to exist for the residues Cys, Trp, and His which may play an important role in determining the chaperone structures. Unlike globular proteins, it has been observed that a one-to-one correspondence between the amino acid distribution in a sequence and the structures of molecular chaperones. The preference of amino acid residues surrounding all 20 types of residues in secondary structures and their accessible surface areas have been analysed.

Solvent accessibility analysis on the mutants of Hsc70 ATPase fragment

Molecular chaperones are the cellular proteins which mediate the correct folding of other polypeptides. The concept of solvent accessibility is one of the most powerful tools to understand the structure and stability of protein molecules. The hydrophobic variation of amino acid residues due to point mutations at many active sites of chaperone protein Hsc70 using solvent accessibility analysis is carried out. The numerical indices for several properties of amino acid residues, such as, reduction in accessibility, preference of amino acid residues in interior and surface parts, transfer free energy and the preference of amino acid residues to change their positions (buried/exposed) due to amino acid substitutions for Hsc70 and its mutants were set up. The accessibility of amino acid residues varies much between native and mutant proteins whereas there is no major changes on their conformations. The conformational stability for Hsc70 and its mutants were established and the computed hydrophobic free energy change is around 10 kcal/mol due to single amino acid substitution.

CRYSTAL STRUCTURE AND CONFORMATION OF TWO SIMILAR PIPERIDONES

N-Chloroacetyl-3,5-dimethyl-2,6-diphenylpiperidin-4-one(CADMPO), C21H22ClNO2, F.W=355.85, monoclinic, P21, a=8.2082(10)u2009Å, b=10.4889(10)u2009Å, c=10.6175(10)u2009Å, β=91.833(10)°, V=913.73(17)u2009Å3, Z=2, Dcalc=1.293u2009Mg/m3, μ=1.953u2009mm−1, F000=376, CuKα=1.5418u2009Å, final R1 and wR2 are 0.0399 and 0.0911, respectively N-Chloroacetyl-3-ethyl-2,6-diphenylpiperidin-4-one (CAEPO), C21H22ClNO2, F.W=355.85, monoclinic, P21/n, a=10.3626(6)u2009Å, b=8.5702(5)u2009Å, c=21.6930(10)u2009Å, β=92.25(1)°, V=1925.06(18)u2009Å3, Z=8, Dcalc=1.228u2009Mg/m3, μ=0.211u2009mm−1, F000=752, MoKα=0.71073u2009Å, final R1 and wR2 are 0.0623 and 0.1397, respectively. Crystal structure studies of these two 4-piperidones show that the piperidones adopt twist-boat conformation. The C–H…O type of intermolecular interactions play a role in stabilizing the molecules in the unit cell in addition to van der Waals forces.

CRYSTAL STRUCTURE AND CONFORMATION OF A PAIR OF PIPERIDINE DERIVATIVES

N-Morpholinoacetyl-3-methyl-2,6-diphenylpiperidin-4-one(MCAMPO), C 24 H 28 N 2 O 3 , F.W = 392.48, monoclinic, P2 1 /c, α = 9.5714(10) A, b = 19.7588(10)A, c = 11.3961(10)A, β = 94.383(10)°, V = 2148.9(3)A 3 , Z = 4, D calc = 1.213 Mg/m 3 , μ = 0.639 mm -1 , F 000 = 840, CuKα = 1.5418 A, final R1 and wR2 are 0.0509 and 0.1352, respectively. N-Morpholinoacetyl-3-isopropyl-2,6-diphenylpiperidin-4-one(MCAIPO), C 26 H 32 N 2 O 3 , F.W = 420.54, orthorhombic, P2 1 2 1 2 1 , α = 9.0053(2) A, b = 12.1942(10) A c = 21.1742(2) A, V = 2325.19(6)A 3 , Z = 4, D calc = 1.201 Mg/m 3 , μ = 0.078 mm -1 , F 000 = 904, MoKα = 0.71073A final R1 and wR2 are 0.0595 and 0.1151, respectively. The heterocyclic rings of the two ketopiperidines exhibit twist-boat and chair conformations, respectively. The morpholine ring poses an acceptor nitrogen atom for C-H...N interactions in both the structures.

Crystal Structures of a Pair of Benzothiazepines

N-Formyl-2,3,4,5-tetrahydro-2,4-diphenyl-1,5-benzothiazepine(FDPBT), C 22 H 19 N O S, F.W=345.44, monoclinic, P2 1 /c, a=11.2268(1)Å, b=9.0297(1)Å, c=18.3813(1) Å, g =104.77(1), V=1801.8(3) Å 3 , Z=4, D calc =1.273 Mg/m 3 , w =1.651 mm m 1 , F 000 =728, CuK f =1.5418 Å, final R1 and wR2 are 0.0757 and 0.1752, respectively. N-Chloroacetyl-2,3,4,5-tetrahydro-2,2,4-trimethyl-1,5-ben-zothiazepine(CTMBT), C 14 H 17 Cl N O S, F.W=282.80, monoclinic, P21/c, a= 12.9740(1)Å, b=13.3530(1) Å, c=17.0790(1) Å, g =91.12(1), V=2958.2(4)Å 3 , Z=8, D calc =1.270 Mg/m 3 , w =3.504 mm m 1 , F 000 =1192, CuK f =1.5418 Å, final R1 and wR2 are 0.0610 and 0.1609, respectively. The septilateral ring of the benzothiazepine in the two structures adheres to an identical boat conformation. The prow and stern angles are nearly the same for both the medium-sized rings.