Biology Reference
In-Depth Information
necessitates only one NMA for the wild-type system and is thus much
faster. It is based on the idea that the most important contributions to
S
vib
originate from side chains which contribute most to the vibrational
amplitude.
Recently, the CMEPS (computational mutations to estimate protein
stability) approach
61
has been introduced. It uses MM-GBSA calculations
to study the impact of mutations on protein structural stability and deter-
mine the most important residues for the protein fold. It is based on the
notion that the
G
bind
corresponding to the alchemical complexation of
a given side chain (considered as a pseudo-ligand) into the rest of the
protein (considered as a pseudo-receptor) reflects the importance of this
side chain to the thermodynamic stability of the protein. This method
has been applied successfully to the study of insulin,
61
p53,
62
and PPAR
63
structural stability.
∆
5. Examples of Applications
To illustrate the application of some of these techniques to biological and
medical questions, we will review some projects recently developed at the
Molecular Modeling Group of the SIB.
5.1. Protein Design
The specific cellular immune response is based on the recognition by
cytotoxic T lymphocytes (CTLs) of an immunogenic peptide (p) pre-
sented at the surface of the target cell by a class I major histocompatibil-
ity complex (MHC; see Fig. 6). Binding of the T cell receptor (TCR) to
the p-MHC complex results in activation of the CTLs and target cell
destruction. Because of the central role of the T lymphocyte in the
immune response, the molecular basis of the interaction between the
TCR and the p-MHC is of general interest in immunology and medicine,
and more specifically in cancer immunotherapy. The major determinant of
T cell activation is the affinity of the TCR for the p-MHC complex,
though kinetic parameters are also important. Therefore, methods aimed
at understanding the role played by each residue in the recognition
between the different components of the TCR-p-MHC complex, not
