Biodynamics: A novel quasi-first principles theory on the fundamental mechanisms of cellular function/dysfunction and the pharmacological modulation thereof

Cellular function depends on heterogeneous dynamic intra-, inter-, and supramolecular structure-function relationships. However, the specific mechanisms by which cellular function is transduced from molecular systems, and by which cellular dysfunction arises from molecular dysfunction are poorly und...

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Published in:	PloS one 2018-11, Vol.13 (11), p.e0202376-e0202376
Main Authors:	Selvaggio, Gianluca, Pearlstein, Robert Alan
Format:	Article
Language:	eng
Subjects:	Algorithms Analysis Binding Sites Biodynamics Biology and Life Sciences Biomedical research Cellular structure Computing time Decay Decay rate Differential equations Drug Discovery - methods Energy Enzymes Equilibrium Equivalence First principles Fluxes Heparan sulfate Humans Kinetics Ligands Medicine and Health Sciences Molecular modelling Ordinary differential equations Pharmacology Physical Sciences Potassium Protein Binding Proteins Proteins - chemistry Proteins - metabolism R&D Research & development Research and Analysis Methods Structure-function relationships Thermodynamics Time dependence
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Summary:	Cellular function depends on heterogeneous dynamic intra-, inter-, and supramolecular structure-function relationships. However, the specific mechanisms by which cellular function is transduced from molecular systems, and by which cellular dysfunction arises from molecular dysfunction are poorly understood. We proposed previously that cellular function manifests as a molecular form of analog computing, in which specific time-dependent state transition fluxes within sets of molecular species ("molecular differential equations" (MDEs)) are sped and slowed in response to specific perturbations (inputs). In this work, we offer a theoretical treatment of the molecular mechanisms underlying cellular analog computing (which we refer to as "biodynamics"), focusing primarily on non-equilibrium (dynamic) intermolecular state transitions that serve as the principal means by which MDE systems are solved (the molecular equivalent of mathematical "integration"). Under these conditions, bound state occupancy is governed by kon and koff, together with the rates of binding partner buildup and decay. Achieving constant fractional occupancy over time depends on: 1) equivalence between kon and the rate of binding site buildup); 2) equivalence between koff and the rate of binding site decay; and 3) free ligand concentration relative to koff/kon (n · Kd, where n is the fold increase in binding partner concentration needed to achieve a given fractional occupancy). Failure to satisfy these conditions results in fractional occupancy well below that corresponding to n · Kd. The implications of biodynamics for cellular function/dysfunction and drug discovery are discussed.
ISSN:	1932-6203 1932-6203