Cooperative structural transitions induced by non-homogeneous intramolecular interactions in compact globular proteins

Abstract

The role played by non-homogeneous interactions in stabilizing cooperative structural changes in proteins was investigated by exhaustive simulations of all compact conformations compatible with several well-defined globule-like shapes in three dimensions. Conformational free energies corresponding to the association of residues i and j were computed both for the unperturbed system, all subject to identical intramolecular interactions, and for the perturbed system in which a single pair of residues is probed by changing its interactions with an attractive or repulsive interaction. The high packing density leads to strong coupling between residues so that specific interactions between a given pair of residues are accompanied by considerable enthalpy changes. Relatively weak, about 1-2 kcal/mol, attractive interactions can exert a dramatic effect on the free energy distribution. Usually, central positions in the sequence most affect the conformational characteristics. Some of these interaction pairs appear to be capable of effecting major conformation transitions because of the high level of cooperativity in the dense state. Effects of repulsive interactions, however, do not depend so strongly on residue pair and cause more localized structural changes. This approach can suggest more, or less, sensitive loci for amino acid substitution.

Understanding the recognition of protein structural classes by amino acid composition

“…As a first step, an exhaustive enumeration of all conformations compatible with a given 3-D shape is made. 24 We note that in an n ϫ n ϫ n cubic lattice all conformations have equal numbers of contacts, n ϩ n 1/3 Ϫ 2n 2/3 , and the factor distinguishing the conformations is their distribution of non-bonded contacts, i.e., the distribution of coordination numbers, and the size and geometry of clusters of sites in close contact.…”

Computational Ways to Enhance Protein Inhibitor Design

“…Elastic Network Models of proteins, such as the Gaussian Network Model (GNM) and Anisotropic Network Models (ANM) of proteins as developed by Tirion ( 1996 ), Bahar, Erman, and Jernigan (Bahar and Jernigan, 1994 , 1998 ; Bahar et al, 1997a ; Demirel et al, 1998 ; Atilgan et al, 2001 ; Doruker et al, 2002a , b ; Doruker and Jernigan, 2003 ; Sen et al, 2006 ), computationally yield information about protein fluctuation dynamics, the directions of motions of the residues and atoms around their equilibrium positions. This information has already been used by Bahar, Jernigan, Kloczkowski, and many others with significant success (Bahar and Jernigan, 1994 ; Keskin et al, 2002a , b ; Isin et al, 2012 ) to explain functional motions and mechanisms in proteins, nucleic acids, and large biological assemblies, such as the ribosome. ANM could be used as an alternative to calculate the normal modes from a single structure when insufficient numbers of experimental structures or structures having sufficient variability are not available to perform PC analysis, then normal modes from the elastic network models could also be used to compute entropies (Zimmermann et al, 2012 ) (But, as we show below, contact entropies are simpler and provide significant gains).…”

Efficient Method To Count and Generate Compact Protein Lattice Conformations

“…Globular proteins differ from random coils in having dense, compact cores partly as a result of the segregation between hydrophobic and polar residues. Because of their dense cores, compact self-avoiding walks (chains) on lattices provide an excellent model for globular proteins. − A compact self-avoiding walk is defined here as a self-avoiding walk with a compact shape, such that all sites within the shape are occupied; there can be no voids. With the self-avoiding walk method it is theoretically possible to generate and enumerate all possible compact conformations within a given volume, but the time required for computations grows geometrically with the length of the chain …”