Role of Resultant Dipole Moment in Mechanical Dissociation of Biological Complexes

Abstract

Protein-peptide interactions play essential roles in many cellular processes and their structural characterization is the major focus of current experimental and theoretical research. Two decades ago, it was proposed to employ the steered molecular dynamics (SMD) to assess the strength of protein-peptide interactions. The idea behind using SMD simulations is that the mechanical stability can be used as a promising and an efficient alternative to computationally highly demanding estimation of binding affinity. However, mechanical stability defined as a peak in force-extension profile depends on the choice of the pulling direction. Here we propose an uncommon choice of the pulling direction along resultant dipole moment (RDM) vector, which has not been explored in SMD simulations so far. Using explicit solvent all-atom MD simulations, we apply SMD technique to probe mechanical resistance of ligand-receptor system pulled along two different vectors. A novel pulling direction-when ligand unbinds along the RDM vector-results in stronger forces compared to commonly used ligand unbinding along center of masses vector. Our observation that RDM is one of the factors influencing the mechanical stability of protein-peptide complex can be used to improve the ranking of binding affinities by using mechanical stability as an effective scoring function.

Keywords: all-atom molecular dynamics simulation; mechanical stability; protein-peptide interactions; resultant dipole moment; steered molecular dynamics.

Figure 1

(a) Dependence of the force as a function of extension for stretching of multi-domain protein titin. The peaks correspond to the unfolding of individual domains with maximum resisting force to stretching, F_max. Figure adopted from Ref. [25]; (b) The 3D structure of titin (Brookhaven PDB databank; PDB ID 1TIT). Titin has eight β-strands: A (4–8), A′ (11–15), B (18–25), C (32–36), D (47–52), E (55–61), F (69–75), G (78–88). Each peak in force-extension profile corresponds to the breaking of hydrogen bonds between beta-strands marked by red color.

Figure 2

Examples of force-extension profiles for 2LLO complex pulled in different directions (b). Green and blue colors refer to the resultant dipole moment (RDM) and COMs pulling directions, respectively. The native conformation of 2LLO is shown on the left (marked by NS) with ligand colored red and receptor colored black. Representative snapshots of pathways for the mechanical unfolding along COMs and RDM directions are shown at the top (a) and bottom (c), respectively. In representative snapshots, we show the position of ligand in native conformation in transparent red.

Figure 3

Histograms of rupture forces for 2LLO peptide-protein complex along RDM (green) and COM (blue) directions. The histograms clearly show that force peak moves towards higher values for RDM vector compared to COMs one.

Figure 4

The native conformations of 1DDV (a) and 1JD5 (b) complexes with ligand colored red and receptor colored black. Green and blue colors refer to the resultant dipole moment (RDM) and COMs pulling directions, respectively. Histograms of rupture forces for 1DDV (c) and 1JD5 (d) peptide-protein complexes along RDM (green) and COMs (blue) directions.