The Need for Consistency with Physical Laws and Logic in Choosing Between Competing Molecular Mechanisms in Biological Processes: A Case Study in Modeling ATP Synthesis.

Traditionally, proposed molecular mechanisms of fundamental biological processes have been tested against experiment. However, owing to a plethora of reasons-difficulty in designing, carrying out, and interpreting key experiments, use of different experimental models and systems, conduct of studies under widely varying experimental conditions, fineness in distinctions between competing mechanisms, complexity of the scientific issues, and the resistance of some scientists to discoveries that are contrary to popularly held beliefs-this has not solved the problem despite decades of work in the field/s. The author would like to prescribe an alternative way: that of testing competing models/mechanisms for their adherence to scientific laws and principles, and checking for errors in logic. Such tests are fairly commonly carried out in the mathematics, physics, and engineering literature. Further, reported experimental measurements should not be smaller than minimum detectable values for the measurement technique employed and should truly reflect function of the actual system without inapplicable extrapolation. Progress in the biological fields would be greatly accelerated, and considerable scientific acrimony avoided by adopting this approach. Some examples from the fundamental field of ATP synthesis in oxidative phosphorylation (OXPHOS) have been reviewed that also serve to illustrate the approach. The approach has never let the author down in his 35-yr-long experience on biological mechanisms. This change in thinking should lead to a considerable saving of both time and resources, help channel research efforts toward solution of the right problems, and hopefully provide new vistas to a younger generation of open-minded biological scientists.