Steered Molecular Dynamics Simulations for Studying Protein–Ligand Interaction in Cyclin-Dependent Kinase 5

Abstract

In this study, we applied steered molecular dynamics (SMD) simulations to investigate the unbinding mechanism of nine inhibitors of the enzyme cyclin-dependent kinase 5 (CDK5). The study had two major objectives: (i) to create a correlation between the unbinding force profiles and the inhibition activities of these compounds expressed as IC50 values; (ii) to investigate the unbinding mechanism and to reveal atomistic insights, which could help identify accessory binding sites and transient interactions. Overall, we carried out 1.35 μs of cumulative SMD simulations. We showed that SMD could qualitatively discriminate binders from nonbinders, while it failed to properly rank series of inhibitors, particularly when IC50 values were too similar. From a mechanistic standpoint, SMD provided useful insights related to transient and dynamical interactions, which could complement static description obtained by X-ray crystallography experiments. In conclusion, the present study represents a further step toward a systematic exploitation of SMD and other dynamical approaches in structure-based drug design and computational medicinal chemistry.

Unbiased free energy estimates in fast nonequilibrium transformations using Gaussian mixtures

“…In the last decade, with the advent of massively parallel high performance computing (HPC), the Jarzynski relation has had a significant impact [4][5][6][7][8][9][10][11] in the free energy calculations on large scale biological system and in condensed phases in general. This is due to the fact that the parallel computation of the average Eq.…”

“…17 One possibility to partially cure this pathology is that of performing a small amount of longer less dissipative trajectories, hence diverting part of the parallel resources in speeding up these slow trajectories (double layer parallelism). This is the approach commonly used in the potential of mean force based (PMF) calculation of drug-receptor system [4][5][6][7][8][9] where the drug is mechanically driven along a selected collective coordinate λ from the binding pocket to the bulk solvent in a time in the order of nanoseconds. The bias in this case is mitigated but is by no means suppressed.…”

Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamics simulations and MM/PBSA methods

“…[20] applied the molecular docking and 3D-QSAR modeling (CoMFA and CoMSIA) to reveal the important interactions between the receptor active site residues and compound's functional groups and to understand the binding orientation. Cavalli et al [21] investigated protein−ligand interaction in CDK5 in terms of steered molecular dynamics simulations. Ji et al [22] studied the selectivity of paullones inhibiting GSK-3 rather than CDK5 based on molecular dynamics simulations and free-energy calculations, revealing that paullones could be used as potent selective inhibitors.…”

“…Molecular dynamics (MD) simulation [21,22,24,25] can be used to solve the above problem in terms of experimental results.…”

Study of protein structural deformations under external mechanical perturbations by a coarse-grained simulation method

“…Specific methodology, known as steered molecular dynamics (SMD), was developed to study mechanical properties of proteins deformed by external forces (Gao et al 2006). It has been successfully applied to many molecular systems during the last decade (Isralewitz et al 2001;Genchev et al 2009;Kalyaanamoorthy and Chen 2014;Martin et al 2014;Patel et al 2014).…”