<p>The correct balance between
hydrophobic London dispersion (LD) and peptide hydrogen bonding interactions
must be attained for proteins to fold correctly. To investigate these important
contributors we sought a comparison of the influenza A transmembrane M2 protein (M2TM) 25-residues monomer and
the 25-Ala (Ala<sub>25</sub>)
peptide, used as reference since alanine is the only amino acid forming a
standard peptide helix which is stabilized by the backbone peptide hydrogen bonding interactions. Folding molecular dynamics (MD) simulations were performed ing the AMBER99SB-STAR-ILDN force field
in trifluoroethanol (TFE) as a
membrane mimetic, to study the α-helical stability of M2TM and Ala<sub>25</sub>
peptides. It was shown that M2TM
peptide did not form a single stable α-helix compared to Ala<sub>25</sub>. Instead
appears to be dynamic in nature and quickly inter-converts between an ensemble
of various folded helical structures having the highest thermal stability to
the N-terminal compared to Ala<sub>25</sub>. Circular dichroism (CD) experiments confirm
the stability of the α-helical M2TM. DFT
calculations results revealed an extra stabilization for the folding of M2TM from
b-strand to the α-helix compared to Ala<sub>25</sub>, due to forces that can't be
described from a force field. On a technical level, calculations using D95(d,p)
single point at a ONIOM (6-31G,3-21G) minimized geometry, in which the backbone
is calculated with 6-31G and alkyl side chains with 3-21G, produced an energy
differential for M2TM comparable with full D95(d,p). Natural bond orbital (NBO)
and quantum theory of atoms in molecules (QTAIM)
calculations were applied to investigate the relative contribution of N-H∙∙∙O as
compared to C-H∙∙∙O hydrogen bonding interactions in the M2TM which included 17
lipophilic residues; 26 CH∙∙∙O interactions were identified, as compared to 22
NH∙∙∙O H-bonds. The calculations suggested that CH∙∙∙O hydrogen bonds, although
individually weaker, have a cumulative effect that cannot be ignored and may contribute
as much as half of the total interaction energy when compared to NH∙∙∙O to the
stabilization of the folded α-helix in M2TM compared to Ala<sub>25</sub>.</p>
Simulating Absorption Spectra of Flavonoids in Aqueous Solution: A Polarizable QM/MM Study
