Robert Pearlstein, PhD

Robert Pearlstein, Global Discovery Chemistry

Global Discovery Chemistry

Cambridge, Massachusetts, United States

We are exploring the fundamental mechanisms by which molecular function is transduced into cellular function, and by which cellular dysfunction arises from molecular dysfunction, based on a theoretical approach that we refer to as “biodynamics.” Under this framework, cellular function is attributed to a molecular form of analog computing, in which:1) differential equations are modeled physically by the rates of various types of molecular state transitions (which we refer to as “molecular differential equations”); 2) sets of coupled “molecular differential equations” (MDEs) are integrated (i.e., “solved”) by way of interdependent dynamic behaviors (i.e., convergent properties of the system); and 3) MDEs are slowed or sped individually based on their intrinsic response to the convergent properties (constituting a recursive feedback loop). State transition fluxes depend on non-equilibrium conditions resulting from the continuous production and degradation of molecular species, which drive.

State transition fluxes depend on non-equilibrium conditions resulting from the continuous production and degradation of molecular species, which drive unidirectional flow of the processes. States are populated according to their rates of entry (i.e., buildup) and exit (i.e., decay), rather than free energy differences. The rates of state transition fluxes are governed by kinetic barriers that determine the rates of entry and exit to/from each state. We were among the first to attribute kinetic barriers to desolvation and resolvation costs (principally H-bond losses) due to solute rearrangement-induced water transfer. Over- and undershooting due to obligatory exponential buildup and decay of molecular levels and states is circumvented by “dynamic counter-balancing” (which we refer to as “Yin-Yang”). Disease may be attributed to Yin-Yang imbalances, resulting in abnormally high or low MDE modulation.

The reduction to practice of our theory consists of multi-scale simulations at the atomistic (WATMD simulations) and atom-less (KinetEx simulations) system levels. We have used a published cardiac action potential model as a testbed for dissecting the specific mechanisms by which MDEs are constructed, coupled, and integrated, and along the way, have explained the detailed mechanistic basis of arrhythmogenesis in cardiomyocytes. We have also developed an automated dynamic simulation software package (KinetEx), which we have thus far used to dissect the biodynamic basis of MAP kinase function. We are currently working to explain other cellular functions on the basis of biodynamics/cellular computing, as well as pharmacodynamic mitigation of cellular dysfunction (which is aimed hypothetically at the restoration of Yin-Yang imbalances).

Selected Publications

New insights about the mechanisms of early afterdepolarizations derived from simulations of cardiac action potentials using the O’Hara-Rudy model.
Selvaggio G, Pearlstein RA.
In late stage preparation.

Biodynamics: A novel first principles theory on the fundamental mechanisms of cellular function/dysfunction and the pharmacological modulation thereof.
Selvaggio G, Pearlstein RA.
In late stage preparation.

Building new bridges between in vitro and in vivo in early drug discovery: where molecular modeling meets systems biology.
Pearlstein RA, McKay D, Velez-Vega C, Hornak V, Dickson C, Golosov A, Harrison T, Duca J.
Current Topics in Medicinal Chemistry. 2017 Apr; 17: 2642-2662.

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