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BDflex: a method for efficient treatment of molecular flexibility in calculating protein-ligand binding rate constants from brownian dynamics simulations.

ABSTRACT: A method developed by Northrup et al. [J. Chem. Phys. 80, 1517 (1984)] for calculating protein-ligand binding rate constants (k(a)) from brownian dynamics (BD) simulations has been widely used for rigid molecules. Application to flexible molecules is limited by the formidable computational cost to treat conformational fluctuations during the long BD simulations necessary for k(a) calculation. Here, we propose a new method called BDflex for k(a) calculation that circumvents this problem. The basic idea is to separate the whole space into an outer region and an inner region, and formulate k(a) as the product of k(E) and η(d), which are obtained by separately solving exterior and interior problems. k(E) is the diffusion-controlled rate constant for the ligand in the outer region to reach the dividing surface between the outer and inner regions; in this exterior problem conformational fluctuations can be neglected. η(d) is the probability that the ligand, starting from the dividing surface, will react at the binding site rather than escape to infinity. The crucial step in reducing the determination of η(d) to a problem confined to the inner region is a radiation boundary condition imposed on the dividing surface; the reactivity on this boundary is proportional to k(E). By confining the ligand to the inner region and imposing the radiation boundary condition, we avoid multiple-crossing of the dividing surface before reaction at the binding site and hence dramatically cut down the total simulation time, making the treatment of conformational fluctuations affordable. BDflex is expected to have wide applications in problems where conformational fluctuations of the molecules are crucial for productive ligand binding, such as in cases where transient widening of a bottleneck allows the ligand to access the binding pocket, or the binding site is properly formed only after ligand entrance induces the closure of a lid.

SUBMITTER: Greives N

PROVIDER: S-EPMC3477184 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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Project description:Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, the docking scores are not sufficiently precise to represent the protein-ligand binding affinity. Here, we developed an efficient computational method for calculating protein-ligand binding affinity, which is based on molecular mechanics generalized Born/surface area (MM-GBSA) calculations and Jarzynski identity. Jarzynski identity is an exact relation between free energy differences and the work done through non-equilibrium process, and MM-GBSA is a semimacroscopic approach to calculate the potential energy. To calculate the work distribution when a ligand is pulled out of its binding site, multiple protein-ligand conformations are randomly generated as an alternative to performing an explicit single-molecule pulling simulation. We assessed the new method, multiple random conformation/MM-GBSA (MRC-MMGBSA), by evaluating ligand-binding affinities (scores) for four target proteins, and comparing these scores with experimental data. The calculated scores were qualitatively in good agreement with the experimental binding affinities, and the optimal docking structure could be determined by ranking the scores of the multiple docking poses obtained by the molecular docking process. Furthermore, the scores showed a strong linear response to experimental binding free energies, so that the free energy difference of the ligand binding (??G) could be calculated by linear scaling of the scores. The error of calculated ??G was within ? ± 1.5 kcal.mol(-1) of the experimental values. Particularly, in the case of flexible target proteins, the MRC-MMGBSA scores were more effective in ranking ligands than those generated by the MM-GBSA method using a single protein-ligand conformation. The results suggest that, owing to its lower computational costs and greater accuracy, the MRC-MMGBSA offers efficient means to rank the ligands, in the post-docking process, according to their binding affinities, and to compare these directly with the experimental values.

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BDflex: a method for efficient treatment of molecular flexibility in calculating protein-ligand binding rate constants from brownian dynamics simulations.

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