Dataset Information

Bridging solvent molecules mediate RNase A - Ligand binding.

ABSTRACT: Due to its high catalytic activity and readily available supply, ribonuclease A (RNase A) has become a pivotal enzyme in the history of protein science. Moreover, this great interest has carried over to computational chemistry and molecular dynamics, where RNase A has become a model system for various types of studies, all the while being an important drug design target in its own right. Here, we present a detailed molecular dynamics study of RNase-ligand binding involving 22 compounds, spanning nearly five orders of magnitude in affinity, and totaling 8.8 ?s of sampling with the standard Amber parameters and an additional 8.8 ?s of sampling with a modified potential. We show that short-lived, solvent-mediated bridging interactions are crucial to RNase-ligand binding. We characterize the behavior of bridging solvent molecules, uncovering a power-law dependence between the lifetime of a solvent bridge and the probability of its occurrence. We also demonstrate that from an energetic perspective, bridging solvent in RNase A-ligand binding behaves like part of the enzyme, rather than the ligands. Moreover, we describe an automated pipeline for the detection and processing of bridging interactions, and offer an independent assessment of the performance of the state-of-the-art fixed-charge force fields. Thus, our work has broad implications for drug design and computational chemistry in general.

SUBMITTER: Ivanov SM

PROVIDER: S-EPMC6808499 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Bridging solvent molecules mediate RNase A - Ligand binding.

Ivanov Stefan M SM Dimitrov Ivan I Doytchinova Irini A IA

PloS one 20191023 10

Due to its high catalytic activity and readily available supply, ribonuclease A (RNase A) has become a pivotal enzyme in the history of protein science. Moreover, this great interest has carried over to computational chemistry and molecular dynamics, where RNase A has become a model system for various types of studies, all the while being an important drug design target in its own right. Here, we present a detailed molecular dynamics study of RNase-ligand binding involving 22 compounds, spanning ...[more]

PMID: 31644593

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Project description:Ligand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (T4L L99A) that rapidly binds benzene (~106 M-1s-1). Although the protein has long served as a model system for protein thermodynamics and crystal structures of both free and benzene-bound T4L L99A are available, the kinetic pathways by which benzene reaches its solvent-inaccessible binding cavity remain elusive. The current work, using extensive molecular dynamics simulation, achieves this by capturing the complete process of spontaneous recognition of benzene by T4L L99A at atomistic resolution. A series of multi-microsecond unbiased molecular dynamics simulation trajectories unequivocally reveal how benzene, starting in bulk solvent, diffuses to the protein and spontaneously reaches the solvent inaccessible cavity of T4L L99A. The simulated and high-resolution X-ray derived bound structures are in excellent agreement. A robust four-state Markov model, developed using cumulative 60 μs trajectories, identifies and quantifies multiple ligand binding pathways with low activation barriers. Interestingly, none of these identified binding pathways required large conformational changes for ligand access to the buried cavity. Rather, these involve transient but crucial opening of a channel to the cavity via subtle displacements in the positions of key helices (helix4/helix6, helix7/helix9) leading to rapid binding. Free energy simulations further elucidate that these channel-opening events would have been unfavorable in wild type T4L. Taken together and via integrating with results from experiments, these simulations provide unprecedented mechanistic insights into the complete ligand recognition process in a buried cavity. By illustrating the power of subtle helix movements in opening up multiple pathways for ligand access, this work offers an alternate view of ligand recognition in a solvent-inaccessible cavity, contrary to the common perception of a single dominant pathway for ligand binding.

Dataset Information

Bridging solvent molecules mediate RNase A - Ligand binding.

Publications

Bridging solvent molecules mediate RNase A - Ligand binding.

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