Ab-initio binding of barnase–barstar with DelPhiForce steered Molecular Dynamics (DFMD) approach

Abstract

Receptor–ligand interactions are involved in various biological processes, therefore understanding the binding mechanism and ability to predict the binding mode are essential for many biological investigations. While many computational methods exist to predict the 3D structure of the corresponding complex provided the knowledge of the monomers, here we use the newly developed DelPhiForce steered Molecular Dynamics (DFMD) approach to model the binding of barstar to barnase to demonstrate that first-principles methods are also capable of modeling the binding. Essential component of DFMD approach is enhancing the role of long-range electrostatic interactions to provide guiding force of the monomers toward their correct binding orientation and position. Thus, it is demonstrated that the DFMD can successfully dock barstar to barnase even if the initial positions and orientations of both are completely different from the correct ones. Thus, the electrostatics provides orientational guidance along with pulling force to deliver the ligand in close proximity to the receptor.

Electrostatics in Computational Biophysics and Its Implications for Disease Effects

“…To overcome such limitations, a hybrid method involving DelPhi [ 48 , 49 , 50 , 51 ] (a popular Poisson–Boltzmann equation solver) and steered MD was developed. The method, termed DelPhi–Force MD (DFMD) [ 10 , 52 ], was successfully applied to dock substrates to an enzyme [ 2 ] and a biomolecule onto another biomolecule (such as barstar onto barnase) [ 10 ]. It was demonstrated that such an approach allows one to take advantage of the MD protocol to sample different conformations while simultaneously adding electrostatic force-based guidance of the ligand toward the correct binding pocket/interface [ 2 ].…”

“…It was demonstrated that such an approach allows one to take advantage of the MD protocol to sample different conformations while simultaneously adding electrostatic force-based guidance of the ligand toward the correct binding pocket/interface [ 2 ]. Moreover, it was shown that DFMD can successfully dock to barnase even if the initial positions and orientations of both are completely different from the correct ones [ 10 ].…”

“…The electrostatic force generates torque that reorients the partners to a proper orientation. This has been demonstrated in a series of examples, including barnase–barstar [ 10 ], dynein–microtubule [ 12 ], and capsomer–capsomer interactions in viral capsid assembly [ 58 ].…”

“…Long-range effects are introduced in Section 2.1 . Such algorithms of long-range electrostatics are widely used in biological problems, such as protein–protein interactions [ 10 , 11 , 12 ], protein–DNA/RNA interactions [ 9 , 13 ], etc. Short-range interactions, including salt bridges and hydrogen bonds, which are favorable interactions in terms of Coulombic energy, are present inside/among the macromolecules, serving as an important feature contributing to macromolecular architecture.…”