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Position-specific propensities of amino acids in the β-strand
BMC Structural Biology
Position-specific propensities of amino acids in the b-strand
Nicholus Bhattacharjee 0
Parbati Biswas 0
0 Department of Chemistry, University of Delhi , Delhi - 110007 , India
Background: Despite the importance of b-strands as main building blocks in proteins, the propensity of amino acid in b-strands is not well-understood as it has been more difficult to determine experimentally compared to a-helices. Recent studies have shown that most of the amino acids have significantly high or low propensity towards both ends of b-strands. However, a comprehensive analysis of the sequence dependent amino acid propensities at positions between the ends of the b-strand has not been investigated. Results: The propensities of the amino acids calculated from a large non-redundant database of proteins are found to be highly position-specific and vary continuously throughout the length of the b-strand. They follow an unexpected characteristic periodic pattern in inner positions with respect to the cap residues in both termini of b-strands; this periodic nature is markedly different from that of the a-helices with respect to the strength and pattern in periodicity. This periodicity is not only different for different amino acids but it also varies considerably for the amino acids belonging to the same physico-chemical group. Average hydrophobicity is also found to be periodic with respect to the positions from both termini of b-strands. Conclusions: The results contradict the earlier perception of isotropic nature of amino acid propensities in the middle region of b-strands. These position-specific propensities should be of immense help in understanding the factors responsible for b-strand design and efficient prediction of b-strand structure in unknown proteins.
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Background
Secondary structural elements like a-helices and
b-strands are important determinants of folded protein
structure and topology. Helices and strands are regular
repetitive structures; while a-helices are
quasi-onedimensional formed by local interactions [1,2], long
b-strands self-assemble into complex hydrogen-bonded
b-sheets by long-range and inter-chain interactions
[3-5]. Secondary structures are predicted on the basis of
statistical analysis of known protein structures, fold
recognition and multiple sequence alignments. Various
close packing arrangements of these strands and helices
are systematically optimized [6] to test the resultant
tertiary structure or a specific fold. It is, therefore,
important to understand the factors dictating the
intrinsic preferences of amino acid residues for a particular
secondary structure [7].
Statistical analysis of known proteins [7,8] clearly
reveals that amino acids have definite conformational
preferences for one or the other type of secondary
structure. Secondary structure prediction methods [9-13]
systematically analyze how these preferences determine
whether a given sequence will adopt an a-helical or a
b-sheet topology or neither. Even the frequencies of
occurrences of amino acid residues in a helix at the
N-terminus end (N-cap), at the C-terminus end (C-cap)
and at interior positions are very different [14-25]. This
non-equivalence of different positions around the helix
termini with respect to amino acid preferences is also
supported by experimental results [26-36]. Though early
studies establish distinct differences in the propensities
of the amino acids at N-cap, N1, N2 and N3 positions
[14,15,37-39], it was assumed that beyond the first few
residues from both the termini, the individual
propensities average out leading to essentially isotropic
environments [16]. An unexpected recent finding confirms that
the sequence dependence of helical propensities at
positions between the ends of helices are markedly different
and they exhibit a distinct pattern throughout the helix
length [40].
Despite the importance of b-strands as main building
blocks in proteins, the propensity of b-strands is not
well-understood as it has been more difficult to
determine experimentally compared to a-helices. This is
attributed to the fact that b-sheets do not fold
independently. Another reason may be the structural context
dependence of the amino acids in b-sheet formation.
A statistical survey of the protein structure database
correlates well with an average of the experimental
scales to determine the b-sheet propensity [41] and
supports the idea that the intrinsic b-sheet propensity plays
a pivotal role in assessing protein stability [42]. Various
factors like the side-chain dependent steric interactions
[43] and solvent screening of the backbone electrostatic
interactions [44] dictate the preference of the amino
acids for b-sheet formation. Conformational entropy
analysis also quantitatively establishes [45] the role of
steric clashes between the side-chain and local backbone
of an amino acid as the dominant cause of intrinsic
b-sheet propensity. Recently, it has been proved that
even the confo (...truncated)