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Protein-protein interaction investigated by steered molecular dynamics: the TCR-pMHC complex.

ABSTRACT: We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered, which only differ by the mutation of a single amino acid on the peptide; one is a strong agonist that produces T cell activation in vivo, while the other is an antagonist. We investigate the interaction mechanism from a large number of unbinding trajectories by analyzing van der Waals and electrostatic interactions and by computing energy changes in proteins and solvent. In addition, dissociation potentials of mean force are calculated with the Jarzynski identity, using an averaging method developed for our steering scheme. We analyze the convergence of the Jarzynski exponential average, which is hampered by the large amount of dissipative work involved and the complexity of the system. The resulting dissociation free energies largely underestimate experimental values, but the simulations are able to clearly differentiate between wild-type and mutated TCR-pMHC and give insights into the dissociation mechanism.

SUBMITTER: Cuendet MA

PROVIDER: S-EPMC2553100 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Protein-protein interaction investigated by steered molecular dynamics: the TCR-pMHC complex.

Cuendet Michel A MA Michielin Olivier O

Biophysical journal 20080711 8

We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered, which only differ by the mutation of a single amino acid on the peptide; one is a strong agonist that produces T cell activation in vivo, while the other is an antagonist. We investigate the interacti ...[more]

PMID: 18621828

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Project description:Computing protein-protein association affinities is one of the fundamental challenges in computational biophysics/biochemistry. The overwhelming amount of statistics in the phase space of very high dimensions cannot be sufficiently sampled even with today's high-performance computing power. In this article, we extend a potential of mean force (PMF)-based approach, the hybrid steered molecular dynamics (hSMD) approach we developed for ligand-protein binding, to protein-protein association problems. For a protein complex consisting of two protomers, P1 and P2, we choose m (≥3) segments of P1 whose m centers of mass are to be steered in a chosen direction and n (≥3) segments of P2 whose n centers of mass are to be steered in the opposite direction. The coordinates of these m + n centers constitute a phase space of 3(m + n) dimensions (3(m + n)D). All other degrees of freedom of the proteins, ligands, solvents, and solutes are freely subject to the stochastic dynamics of the all-atom model system. Conducting SMD along a line in this phase space, we obtain the 3(m + n)D PMF difference between two chosen states: one single state in the associated state ensemble and one single state in the dissociated state ensemble. This PMF difference is the first of four contributors to the protein-protein association energy. The second contributor is the 3(m + n - 1)D partial partition in the associated state accounting for the rotations and fluctuations of the (m + n - 1) centers while fixing one of the m + n centers of the P1-P2 complex. The two other contributors are the 3(m - 1)D partial partition of P1 and the 3(n - 1)D partial partition of P2 accounting for the rotations and fluctuations of their m - 1 or n - 1 centers while fixing one of the m/n centers of P1/P2 in the dissociated state. Each of these three partial partitions can be factored exactly into a 6D partial partition in multiplication with a remaining factor accounting for the small fluctuations while fixing three of the centers of P1, P2, or the P1-P2 complex, respectively. These small fluctuations can be well-approximated as Gaussian, and every 6D partition can be reduced in an exact manner to three problems of 1D sampling, counting the rotations and fluctuations around one of the centers as being fixed. We implement this hSMD approach to the Ras-RalGDS complex, choosing three centers on RalGDS and three on Ras (m = n = 3). At a computing cost of about 71.6 wall-clock hours using 400 computing cores in parallel, we obtained the association energy, -9.2 ± 1.9 kcal/mol on the basis of CHARMM 36 parameters, which well agrees with the experimental data, -8.4 ± 0.2 kcal/mol.

Dataset Information

Protein-protein interaction investigated by steered molecular dynamics: the TCR-pMHC complex.

Publications

Protein-protein interaction investigated by steered molecular dynamics: the TCR-pMHC complex.

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