Chemistry Reference
In-Depth Information
interaction energies of
8.18 kcal/mol for terphenyl binding in calmod-
ulin (Isvoran et al.
2011
) and troponin C respectively (Isvoran et al.
2013
). All these
energies suggest favorable interactions of therphenyl with the three proteins and this
result may be used to gain insights into the underlying molecular mechanisms of
selectivity of these proteins.
Web-based tools used in protein-ligand interaction analysis also take into ac-
count several databases of domain-peptide interactions. One of these databases
is DOMINO, an open-access database (http://mint.bio.uniroma2.it/domino/) com-
prising more than 3900 annotated experiments describing interactions mediated by
protein-interaction domains (Ceol et al.
2006
). BindingDB is another web-accessible
and public database containing measured binding affinities and focusing on the in-
teractions of protein considered to be drug-targets with small, drug-like molecules
(Liu et al.
2007
). Binding DB also allows validation of computational chemistry and
molecular modeling approaches such as docking, scoring and free energy methods.
−
7.98 and
−
9.5
Computational Analysis of Protein-Protein Interactions
Protein-protein interactions play crucial roles in all cellular processes and numerous
computational methods to infer proteins interactions networks have been proposed in
the last decade. The aim of protein-protein interactions study concerns both a better
understanding of the biochemical pathways and the PPIs disruption from therapeutic
reasons. PPIs result in the formation of protein interfaces and molecular surface
complementarity is a concept that also applies in these cases.
The general physicochemical features found in PPIs are based on computational
analysis of crystallographic structures of the protein-protein complexes. A general
description reveals that protein-protein interfaces are typically large having average
areas between 350 and 1600 Å
2
and a hydrophobic character (Janin and Chotia
1990
; Ban et al.
2004
; Fletcher and Hamilton
2006
). They also often are featureless
in comparison to well defined ligand binding pockets and/or cavities.
There two categories of protein-protein interactions: stable or transient interac-
tions, and both types of interactions can be either strong or weak (Byrum et al.
2012
).
Stable interactions are those associated with proteins forming multi-chain complexes,
homo-or hetero-multimers, for example hemoglobin that is a homotetramer. Tran-
sient interactions are temporary in nature requiring a set of conditions that promote
the interaction: conformational changes of the involved proteins, phosphorylation,
methylation, glycosilation or localization to discrete areas of the cell (Ngounou
et al.
2013
). Transient interactions can be fast or slow and usually are reversible.
Transiently interacting proteins are involved in a wide range of cellular processes,
including protein modification, transport, folding, signaling, and cell cycling.
There are many approaches applying for PPIs studies (Ngounou et al.
2013
): bio-
chemical (cross-linking and chemical modification, combined fractionation during
chromatography and coimmunoprecipitation, electrophoresis), biophysical (fluores-
cence resonance-energy transfer, analytical ultracentrifugation, microscopy, mass
spectrometry), genetic and computer-based approaches. Computer-based methods
