arXiv subjects

Ashok Palaniappan

Publications and source records attributed to Ashok Palaniappan.

5 recordsLinked to original sources

arXiv2011

A Surprising Clarification of the Mechanism of Ion-channel Voltage-Gating

An intense controversy has surrounded the mechanism of voltage-gating in ion channels. We interpreted the two leading models of voltage-gating with respect to the thermodynamic energetics of membrane insertion of the voltage-sensing 'module' from a comprehensive set of potassium channels. KvAP is an archaeal voltage-gated potassium channel whose x-ray structure was the basis for determining the general mechanism of voltage-gating. The free energy of membrane insertion of the KvAP voltage sensor was revealed to be a single outlier. This was due to its unusual sequence that facilitated large gating movements in its native lipid membrane. This degree of free energy was the least typical of the other voltage sensors, including the Shaker potassium channel. We inferred that the two leading models of voltage-gating referred to alternative mechanisms of voltage-gating: each is applicable to an independent set of ion channels. The large motion of the voltage-sensor during gating proposed by the KvAP-paddle model of gating is unlikely to be mirrored by the majority of ion channels whose voltage sensors are not located at the membrane-cytoplasm interface in the channel closed state.

q-bio.BM↗

arXiv2009

Evolutionary Analysis of Biological Excitability

Excitability is an attribute of life, and is a driving force in the descent of complexity. Cellular electrical activity as realized by membrane proteins that act as either channels or transporters is the basis of excitability. Electrical signaling is mediated by a wave of action potentials, which consist of synchronous redistribution of ionic gradients down ion channels. Ion channels select for the passage of a particular ion species. Potassium ion channels are gated by a variety of stimuli, including membrane voltage. Sodium and calcium channels are gated only by membrane voltage, suggesting the conservative argument that voltage-gated potassium channels are the founding members of the voltage-gated ion channel superfamily. The principal focus of this work is the investigation of the complement of potassium ion channels in our genome and its generalizabilty. An array of issues relevant to excitability is addressed, and a range of engagement in questions regarding the unity of life is proffered.

q-bio.BM↗

arXiv2007

Detection of an ancient principle and an elegant solution to the protein classification problem

This work is concerned with the development of a well-founded, theoretically justified, and least complicated metric for the classification of proteins with reference to enzymes. As the signature of an enzyme family, a catalytic domain is easily fingerprinted. Given that the classification problem has so far seemed intractable, a classification schema derived from the catalytic domain would be satisfying. Here I show that there exists a natural ab initio if nonobvious basis to theorize that the catalytic domain of an enzyme is uniquely informative about its regulation. This annotates its function. Based on this hypothesis, a method that correctly classifies potassium ion channels into their respective subfamilies is described. To put the principle on firmer ground, extra validation was sought and obtained through co-evolutionary analyses. The co-evolutionary analyses reveal a departure from the notion that potassium ion channel proteins are functionally modular. This finding is discussed in light of the prevailing notion of domain. These studies establish that significant co-evolution of the catalytic domain of a gene with its conjoint domain is a specialized, necessary process following fusion and swapping events in evolution. Instances of this discovery are likely to be found pervasive in protein science.

q-bio.GN↗

arXiv2007

Fourier Analysis of Biological Evolution: Concept of Selection Moment

Secondary structure elements of many protein families exhibit differential conservation on their opposing faces. Amphipathic helices and beta-sheets by definition possess this property, and play crucial functional roles. This type of evolutionary trajectory of a protein family is usually critical to the functions of the protein family, as well as in creating functions within subfamilies. That is, differential conservation maintains properties of a protein structure related to its orientation, and that are important in packing, recognition, and catalysis. Here I define and formulate a new concept, called the selection moment, that detects this evolutionary process in protein sequences. A treatment of its various applications is detailed.

q-bio.BM↗

arXiv2006

A robust methodology for inferring physiology of a protein family: application to K+-ion channel family

We are interested in the subtle variations of function among the members of a protein family. A protein family is usually subdivided into subfamilies based on functional differences. Existence of this functional diversity is essential for the successful performance of physiological roles expected of the family. This presents a unique problem: there must be preservation of the active site; simultaneously there should be specificity of protein action according to subfamily. Though the classification into subfamilies is by no means a formalized one, it is most times based on the character of regulation of the primary function. The function of a subfamily is a modification of when the protein performs its function, for example, by changing the protein's sensitivity to regulatory factors. Rarely, a subfamily possesses a function completely different for its family. A study of these details is necessary for understanding the fine-tuning of protein function. I describe a theory for studying subfamily-based functional specificity and then validate it with an example application to deciphering the residue-level basis of fine functional variations in the diverse set of K+-channel subfamilies. I provide specific results that will be useful to channel physiologists, whereas the strategy developed will be widely applicable to problems in comparative and functional genomics.

q-bio.GN↗