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Motor-like Properties of Nonmotor Enzymes.

ABSTRACT: Molecular motors are thought to generate force and directional motion via nonequilibrium switching between energy surfaces. Because all enzymes can undergo such switching, we hypothesized that the ability to generate rotary motion and torque is not unique to highly adapted biological motor proteins but is instead a common feature of enzymes. We used molecular dynamics simulations to compute energy surfaces for hundreds of torsions in three enzymes-adenosine kinase, protein kinase A, and HIV-1 protease-and used these energy surfaces within a kinetic model that accounts for intersurface switching and intrasurface probability flows. When substrate is out of equilibrium with product, we find computed torsion rotation rates up ?140 cycles s^-1, with stall torques up to ?2 kcal mol^-1 cycle^-1, and power outputs up to ?50 kcal mol^-1 s^-1. We argue that these enzymes are instances of a general phenomenon of directional probability flows on asymmetric energy surfaces for systems out of equilibrium. Thus, we conjecture that cyclic probability fluxes, corresponding to rotations of torsions and higher-order collective variables, exist in any chiral molecule driven between states in a nonequilibrium manner; we call this the "Asymmetry-Directionality" conjecture. This is expected to apply as well to synthetic chiral molecules switched in a nonequilibrium manner between energy surfaces by light, redox chemistry, or catalysis.

SUBMITTER: Slochower DR

PROVIDER: S-EPMC5961456 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Motor-like Properties of Nonmotor Enzymes.

Slochower David R DR Gilson Michael K MK

Biophysical journal 20180501 9

Molecular motors are thought to generate force and directional motion via nonequilibrium switching between energy surfaces. Because all enzymes can undergo such switching, we hypothesized that the ability to generate rotary motion and torque is not unique to highly adapted biological motor proteins but is instead a common feature of enzymes. We used molecular dynamics simulations to compute energy surfaces for hundreds of torsions in three enzymes-adenosine kinase, protein kinase A, and HIV-1 pr ...[more]

PMID: 29742410

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Project description:Lewy body diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as ?-synuclein (?S) and amyloid-? (A?) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.

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Motor-like Properties of Nonmotor Enzymes.

Publications

Motor-like Properties of Nonmotor Enzymes.

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