A Life of Biophysics

Biophysics is a way of approaching biological problems through numbers, physical laws, models, and quantitative logic. In a long scientific career, I have seen the formation and fruition of the ion channel concept through biophysical study. Marvelous discoveries were made as our instruments evolved from vacuum tubes to transistors; computers evolved from the size of an entire building to a few chips inside our instruments; and genome sequencing, gene expression, and atom-level structural biology became accessible to all laboratories. Science is rewarding and exhilarating. Expected final online publication date for the Annual Review of Biophysics, Volume 51 is May 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Understanding the interaction of 14-3-3 proteins with hDMX and hDM2: a structural and biophysical study

p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis, and senescence. The p53 pathway has therefore served as the focus for drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localisation, degradation and interactions of their targets in response to phosphorylation. Thus 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced ~20-25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.

A thermodynamic description for physiological transmembrane transport

A general formulation for both passive and active transmembrane transport is derived from basic thermodynamical principles. The derivation takes into account the energy required for the motion of molecules across membranes and includes the possibility of modeling asymmetric flow. Transmembrane currents can then be described by the general model in the case of electrogenic flow. As it is desirable in new models, it is possible to derive other well-known expressions for transmembrane currents as particular cases of the general formulation. For instance, the conductance-based formulation for current turns out to be a linear approximation of the general formula for current. Also, under suitable assumptions, other formulas for current based on electrodiffusion, like the constant field approximation by Goldman, can be recovered from the general formulation. The applicability of the general formulations is illustrated first with fits to existing data, and after, with models of transmembrane potential dynamics for pacemaking cardiocytes and neurons. The general formulations presented here provide a common ground for the biophysical study of physiological phenomena that depend on transmembrane transport.