Hierarchical protein folding pathways: A computational study of protein fragments

Publication Type:

Journal Article

Authors:

Haspel, N.; Tsai, C.J.; Wolfson, H.; Nussinov, R.

Source:

Proteins, Volume 51, p.203-215 (2003)

URL:

http://www.kavrakilab.org/sites/default/files/haspel2003hierarchical-folding-computational-fragments.pdf

Abstract:

We have previously presented a
building block folding model. The model postulates
that protein folding is a hierarchical top-down process.
The basic unit from which a fold is constructed,
referred to as a hydrophobic folding unit,
is the outcome of combinatorial assembly of a set of
“building blocks.” Results obtained by the computational
cutting procedure yield fragments that are in
agreement with those obtained experimentally by
limited proteolysis. Here we show that as expected,
proteins from the same family give very similar
building blocks. However, different proteins can
also give building blocks that are similar in structure.
In such cases the building blocks differ in
sequence, stability, contacts with other building
blocks, and in their 3D locations in the protein
structure. This result, which we have repeatedly
observed in many cases, leads us to conclude that
while a building block is influenced by its environment,
nevertheless, it can be viewed as a standalone
unit. For small-sized building blocks existing
in multiple conformations, interactions with sister
building blocks in the protein will increase the
population time of the native conformer. With this
conclusion in hand, it is possible to develop an
algorithm that predicts the building block assignment
of a protein sequence whose structure is unknown.
Toward this goal, we have created sequentially
nonredundant databases of building block
sequences.Aprotein sequence can be aligned against
these, in order to be matched to a set of potential
building blocks.