Studies On Protein-peptide Interactions Via Molecular Dynamics Simulations

The interactions between the globular protein (domain) and the short linear peptide are called protein-peptide interactions. Protein-peptide interactions are prevalent in vivo and play important roles in the signal transduction, apoptotic, immune system, and other vital life processes. Proteins in these interactions thus become important targets of drug design. Here, on the basis of the researches of others, we made a systematic research on the flexibility of the peptide in the protein-peptide recognition, which is neglected for a long time, via molecular dynamics simulations and energy calculations. In addition, a detailed study on a set of protein-peptide complexes in terms of structures and energies was done. We explained the reasons for the different binding affinities among the complexes at the atomic level via molecular dynamics simulations and energy calculations, and provided the theoretical guidance for the peptide inhibitor design.1. Study on the flexibility of the peptide in the protein-peptide recognition. In order to systematically investigate and quantitatively estimate the importance of the flexibility of the peptide in the protein-peptide recognition, we selected 20 different protein-peptide complexes from the PDB and conducted molecular dynamics simulations and energy calculations for the 20 complexes and 20 unbound peptides separated from the corresponding complexes. The results showed that the configurational entropy penalties of the peptides are much larger than their deformation energies and thus become the main content of the indirect readout energy. This is different from the classical biomolecular recognition in which the deformation energy is the main content of the indirect readout energy. Configurational entropy penalties of fifteen complexes exceed one half of the absolute value of their respective direct readout energies, which demonstrates that the entropy effect of the peptide in the protein-peptide recognition is non-ignorable, and this further proves the importance of the flexibility of the peptide in the protein-peptide recognition. There exists a moderate negative correlation between the configurational entropy penalty and the direct readout energy, which indicates that the size of the configurational entropy penalty is not equal to the size of the entropy effect. In addition, we discussed the influencing factors of the configurational entropy penalty of the peptide, studied the relationship between the average entropy penalty of residue and the secondary structure of the peptide, and studied the relationships of the peptide flexibility with its secondary structure and hydrogen bonds. A statistical study of the amino acid propensities of the unbound peptide flexibility was also done. All these studies provided theoretical foundation for further understanding of the flexibility of the peptide in the protein-peptide recognition.2. Molecular dynamics simulations of the interactions between EHD1 EH domain and multiple peptides. During the investigation of the flexibility of the peptide, three complexes formed between EHD1 EH domain and the peptides containing NPF, DPF, and GPF motifs repectively attracted our attention. Their sequences and structures are very similar while their binding affinities are different. In order to explain why the binding affinities are different, we conducted molecular dynamics simulations, MM/GBSA calculations and energy decompositions for the three complexes. Combined with the alanine scanning experiments via FoldX software, we identified the hot spot residues of the peptides of the three complexes. The analysis was done in terms of structures and energies, and the results provided essential information for peptide inhibitor design. The results showed that the different binding affinities of the EHD1 EH domain for the three peptides are contributed dominantly by the van der Waals interactions, residues of the motifs contribute much more than the flanking residues to the binding and that the intermolecular hydrogen bonds formed between the flanking residues and the protein are the structural basis of enhanced van der Waals interactions of the flanking residues. Thus, the van der Waals interactions and the ability of the flanking residues to form intermolecular hydrogen bonds with protein should be the key considerations of peptide inhibitor design.