A boosted unbiased molecular dynamics method for predicting ligands binding mechanisms: Probing the binding pathway of dasatinib to Src-kinase

Abstract

8Small molecules such as substrates, effectors and drugs play essential roles in biological 9 processes. Knowing their interactions with biomacromolecular targets demands a deep 10 understanding of binding and unbinding mechanisms. Dozens of papers have suggested that 11 discovering of either binding or unbinding events by means of conventional UMD simulation 12 urges a considerable amount of computational resources, therefore, only one who holds a 13 supercomputer can afford such extensive simulations. Capabilities of full atomistic Unbiased 14 Molecular Dynamics (UMD) simulation have been undervalued within the scientific community. 15 Thus, myriads of researchers are impelled to be content with debatable biased MD simulations 16 which seek validation for its preconceived framework. In this work, we present a stratagem to 17 empower everyone to perform UMD simulations of protein-ligand binding and unbinding by 18 typical desktop computers and achieve valuable and high-cost results in nanosecond time scale. 19 Here, we have described kinetics of binding and unbinding of anticancer drug, dasatinib, to c-Src 20 kinase in full atomistic details for the first time. We have attained multiple independent binding 21 and unbinding events occurred in the nano-second timescale, even in times as little as 30 and 22 392.6 ns respectively, without presence of any biasing forces, an achievement that nobody has 23 ever assumed to be possible. 24 Ligand binding and unbinding pathway, Dasatinib, c-Src kinase 26 27 28Small molecule compounds are involved in nearly all cellular mechanisms and studying 29 their roles can unravel secrets behind the scenes. These compounds can trigger cell signaling and 30 metabolic pathways by interacting and binding to certain biomacromolecules like proteins and 31 nucleic acids. Over the last few decades, sophisticated methods such as X-ray crystallography, 32 NMR and electron microscopy revealed numerous structural details of many protein-ligand 33 complexes. However, these complexes are just one or some static poses of a vivid system which 34 its function is completely swayed by its movements and dynamics. Furthermore, in many 35 molecular targets like androgen receptor (PDB ID: 2Q7I) 1 , the binding pocket is buried deep 36 inside the protein structure. The X-ray crystallographic structure doesn't reveal any details about 37 the process of induction and the binding pathway, how the ligand makes an entrance into the 38 protein and how it affects residues on its journey to reach the native binding pose. According to 39 the Food and Drug Administration (FDA), small molecules make up the main proportion of 40 approved drugs on the pharmaceutical market today. Thus, understanding the induction and 41 binding mechanisms of small molecules to their molecular targets can immensely assist 42 researchers to optimize and design much more specific and selective drugs accompanied by 43 extremely low side-effects. Therefore, emergence of a complementary method which can take 44 the advantages of ...

Reconstruction of the binding pathway of an anti-HIV drug, Indinavir, in complex with the HTLV-1 protease by Unaggregated Unbiased Molecular Dynamics simulation

“…As explained in a previous study [15], the route for reconstructing the binding pathway of a ligand to the target protein is divided into separate stages. In each stage, the simulations are carried out by using short replicas.…”

“…The partial charges and force field parameters of the inhibitor molecule were assigned by ACEPYPE [34] with the default setting. The pattern and the details of the VISs were set the same as the previous studies [15], the values of the σ and ε parameters for VISs were set to 0.83 nm and 0.1 kJ.mol -1 , respectively.…”

“…Fast and accurate methods such as Unbiased Molecular Dynamics (UMD) simulations can also be utilized to unravel the binding pathways of small molecule inhibitors to evaluate the efficacy of potential inhibitors and understand their inhibitory mechanisms against a protein target [13-21]. The role of different factors in the binding mechanism has to be thoroughly analyzed and understood, and in the past few years, we have developed an efficient method called Unaggregated Unbiased Molecular Dynamics (UUMD) simulation for this purpose [15]. By introducing repulsive forces between the virtual interaction sites (VIS), which are located on the ligand molecules, we can insert a high concentration of ligand molecules into the simulation box.…”