We use molecular dynamics simulations to understand how proteins move and how this plays a role in their function. Specific examples are shown below.
Reboul CF, Meyer GR, Porebski BT, Borg NA, Buckle AM (2012) Epitope Flexibility and Dynamic Footprint Revealed by Molecular Dynamics of a pMHC-TCR Complex. PLoS Comput Biol 8(3): e1002404. doi:10.1371/journal.pcbi.1002404
When pathogens replicate within a host cell, their proteins are degraded into peptides, which are captured by the major histocompatibility complex (MHC) and brought to the cell surface. The peptide-MHC (pMHC) is surveyed by T cell receptors (TCRs) expressed on the surface of T cells. If the peptide is foreign, the peptide-MHC-TCR interaction initiates an immune response to eliminate the pathogen. However, the combinations of pMHC and TCRs are diverse. We ask how TCRs discriminate between structurally similar pMHCs? We address this by focusing on two MHC molecules that differ by a single change, both bind the same peptide but only one instigates a dominant immune response. Intriguingly, the single difference between the two MHCs does not alter the peptide shape nor does it contact the peptide or TCR. We examined the flexibility of the pMHC-TCR interface using molecular dynamics simu- lations. We observed differences in the peptide and TCR flexibilities that could explain their contrasting physiolo- gies, as well as clues to how the TCR moves atop the MHC in order to ‘scan’ it. Our analysis provides insight into a particular pMHC-TCR interaction not accessible using crystallographic methods, and indicate dynamics may play an influential and perhaps under-appreciated role in other pMHC-TCR systems.
Movie 1: Conformational flexibility of peptide in HLA-B*3501-LPEP and HLA-B*3508-LPEP during MD simulations. The polymorphic (R/L156) residue is shown in green. Static snapshots of the respective simulations are shown in the insets.
Movie 3: Detailed view of contacts made at the interface during the MD simulation of HLA-B*3508-LPEP SB27 TCR complex B. On the left, cartoon showing hydrogen bonds and salt bridges (black dotted lines) at the interface between MHC (grey), peptide (green) and TCR (cyan and yellow); On the right, MHC surface showing the dynamic TCR footprint. The MHC residues being contacted by the TCR are coloured red. The inset shows the corresponding footprint calculated from the crystal structure.
Reboul CF, Porebski BT, Griffin MDW, Dobson RCJ, Perugini MA, Gerrard JA, and Buckle AM (2012) Structural and Dynamic Requirements for Optimal Activity of the Essential Bacterial Enzyme Dihydrodipicolinate Synthase. PLoS Comput Biol 8(6): e1002537. doi:10.1371/journal.pcbi.1002537
Enzyme function requires the specific placement of residues in the active site so that the correct chemistry is available for efficient catalysis. However, the inherent flexibility of proteins can present challenges in fulfilling these stringent requirements. We have investigated the role of flexibility in the enzyme Dihydrodipicolinate synthase (DHDPS), which in E. coli is a homotetramer consisting of a ‘dimer of dimers’, with the catalytic residues found at the tight-dimer interface. It is hypothesized that the tetramer arrangement has evolved to restrict the flexibility at the active site by buttressing together a pair of dimers. In contrast, DHDPS from methicillin resistant Staphylococcus aureus (MRSA) occurs naturally as a dimer yet retains full activity. Using molecular dynamics simula- tions we have investigated the flexibility of dimeric and tetrameric forms of the E. coli and MRSA enzymes, and reveal that optimal activity is achieved by minimizing the inherent dimer flexibility using two different strategies – by either buttressing two dimers together in the case of the E. coli tetrameric enzyme or strengthening and extending the dimer interface in the dimeric MRSA.
Conformational properties of the disease-causing Z variant of alpha1 antitrypsin revealed by theory and experiment. Kass, Knaupp, Bottomley, Buckle. (2012). Biophys. J.102(12):2856-65.
Our investigations identify specific interactions in the breach region of the Z-variant of α1-AT that may play a role in its greater propensity to misfold, aggregate, and thus cause disease, and are consistent with biophysical and structural data that highlight the importance of this region in serpin folding and polymerization.