Understanding selectivity-dependent molecular mechanism of inhibitors towards CDK2 over CDK6 is prominent for improving drug design towards the CDK family. Multiple short molecular dynamics (MD) simulations combined with MM-GBSA approach are adopted to investigate molecular mechanism on binding selectivity of inhibitors X64, X3A, and 4 AU to CDK2 and CDK6. The RMSF analysis and calculations of molecular surface areas indicate that local structural and global flexibility of CDK6 are stronger than that of CDK2. Based on dynamics cross-correlation maps (DCCMs), motion modes of CDK2 and CDK6 produce difference due to associations of X64, X3A, and 4 AU. The calculated binding free energies (BFEs) demonstrate that the compensation between binding enthalpy and entropy of X64, X34, and 4 AU is a key force driving selectivity of inhibitors towards CDK2 over CDK6. This work provides valuable information for designing highly selective inhibitors towards CDK2 and CDK6 and further promotes identification of efficient anticancer drugs in the future. Graphical Abstract

Emerging evidences indicate bromodomain-containing proteins 2 and 4 (BRD2 and BRD4) play critical roles in cancers, inflammations, cardiovascular diseases and other pathologies. Multiple short molecular dynamics (MSMD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method were applied to investigate the binding selectivity of three inhibitors 87D, 88M and 89G towards BRD2 over BRD4. The root-mean-square fluctuation (RMSF) analysis indicates that the structural flexibility of BRD4 is stronger than that of BRD2. Moreover the calculated distances between the C_α atoms in the centres of the ZA_loop and BC_loop of BRD4 are also bigger than that of BRD2. The rank of binding free energies calculated using MM-GBSA method agrees well with that determined by experimental data. The results show that 87D can bind more favourably to BRD2 than BRD4, while 88M has better selectivity on BRD4 over BRD2. Residue-based free-energy decomposition method was utilized to estimate the inhibitor-residue interaction spectrum and the results not only identify the hot interaction spots of inhibitors with BRD2 and BRD4, but also demonstrate that several common residues, including (W370, W374), (P371, P375), (V376, V380) and (L381, L385) belonging to (BRD2, BRD4), generate significant binding difference of inhibitors to BRD2 and BRD4.

Hydrogen bonding interactions of waters with BD1/BD2 and inhibitors play significant roles in inhibitor bindings.

Bromodomains (BRDs) are structurally conserved epigenetic reader modules observed in numerous chromatin- and transcription-associated proteins that have a capability to identify acetylated lysine residues.

We study the process of a semiflexible polymer chain adsorption on to planar surface by the dynamic Monte Carlo (DMC) method, based on the 3D off-lattice model. Both the strength of attractive monomer–surface interaction (ε_a) and bending energy (b) have pronounced effect on the adsorption and shape of semiflexible polymer chain. The semiflexible polymer can just fully adsorb on to the surface at certain ε_a, which is defined as critical ε_a. The essential features of the semiflexible polymer adsorption on to surface are that (i) the critical ε_a increases with increase in b; (ii) the shape of the fully adsorbed semiflexible polymer chain is film-like toroid, and the toroid becomes more and more perfect with increase in b. In addition, the size of toroid and the number of turns of toroid can be controlled by the b and ε_a.

Cyclin-dependent kinase 6 (CDK6) has been identified as a potential drug target in various types of cancers. In our current study, multiple independent molecular dynamics simulations of four separate replicates and computations of binding free energies are carried out to decipher the binding mechanisms of three inhibitors, LQQ, 6ZV, and 0RS, to CDK6. The dynamic analyses indicate that the presence of inhibitors influences conformational alterations, motion modes, and the internal dynamics of CDK6. Binding free energies computed using the molecular mechanics generalized Born surface area (MM-GBSA) approach with four GB models demonstrate that hydrophobic interactions play essential roles in inhibitor–CDK6 binding. The computations of residue-based free energy decomposition verify that the side chains of residues I19, K29, M54, P55, F98, H100, and L152 significantly contribute to inhibitor–CDK6 binding, revealing the critical interaction sites of inhibitors for CDK6. The information revealed in our current study can provide theoretical aids for development of potent inhibitors targeting the CDK family.