{"id":{"repo_id":"rice","oai_identifier":"oai:repository.rice.edu:1911/108400"},"canonical_url":"https://search.dev.ndltd.org/etd/rice/oai:repository.rice.edu:1911/108400","repository":{"repo_id":"rice","name":"Rice University","base_url":"https://repository.rice.edu/server/oai/request"},"display":{"title":"Theoretical Studies of Protein-Protein Interactions","abstract":"Proteins are known to play major roles in most processes taking place inside living cells. Understanding their functions and mechanisms of their action is one of the most important problems in the fields of biochemistry and biophysics. In this work we study a kinase called Extracellular Signal Regulated Kinase 2 (ERK2), which regulates cell cell growth, adhesion, survival and differentiation, and motor protein kinesin-1. First part of this thesis is devoted to a study of ERK2-EtsΔ138 system using variety of techniques from theoretical methods, e.g. First Passage Processes method, to Molecular Dynamics and Brownian Dynamics simulations. We first gain insights into the structure of the ERK2-EtsΔ138 complex. We find that in the lowest energy complex F120 residue of EtsΔ138 occupies ψ2 hydrophobic pocket of the FRS of ERK2 and that helix H0 of EtsΔ138 is destabilized by interaction with ERK2. We then show that in the ERK2 regulation network simultaneous decrease of strengths of all interactions can lead to both decrease or increase of overall activity of ERK2 and therefore there is an optimal strength of interactions that maximizes activity. We then formulate hypothesis that one of the binding sites of ERK2 serves to accelerate protein-protein association. We use theoretical methods and simulations to show that additional binding site can accelerate association of ERK2 and EtsΔ138 by a factors from 3 to 4. The last chapter of this thesis is dedicated to the study of Hereditary Spastic Paraplegia (HSP) which is caused by mutations in neuronal kinesin-1. HSP is a disease that is thought to be caused by slowed intracellular transport by mutated kinesin-1. Two mutations, namely N256S and R280C, were experimentally shown to decrease kinesin's velocity as well as its processivity. We used structure-based Molecular Dynamic simulations to show that these mutations can lead to increased probability of open state of ATP-binding pocket of kinesin, which in its turn can lead to low velocity due to poor catalysis. We also show that in the case of N256S mutation this effect is caused by disruption of interactions between α-helix and switch I and loop L11 of kinesin.","abstract_html":"Proteins are known to play major roles in most processes taking place inside living cells. Understanding their functions and mechanisms of their action is one of the most important problems in the fields of biochemistry and biophysics. In this work we study a kinase called Extracellular Signal Regulated Kinase 2 (ERK2), which regulates cell cell growth, adhesion, survival and differentiation, and motor protein kinesin-1. First part of this thesis is devoted to a study of ERK2-EtsΔ138 system using variety of techniques from theoretical methods, e.g. First Passage Processes method, to Molecular Dynamics and Brownian Dynamics simulations. We first gain insights into the structure of the ERK2-EtsΔ138 complex. We find that in the lowest energy complex F120 residue of EtsΔ138 occupies ψ2 hydrophobic pocket of the FRS of ERK2 and that helix H0 of EtsΔ138 is destabilized by interaction with ERK2. We then show that in the ERK2 regulation network simultaneous decrease of strengths of all interactions can lead to both decrease or increase of overall activity of ERK2 and therefore there is an optimal strength of interactions that maximizes activity. We then formulate hypothesis that one of the binding sites of ERK2 serves to accelerate protein-protein association. We use theoretical methods and simulations to show that additional binding site can accelerate association of ERK2 and EtsΔ138 by a factors from 3 to 4. The last chapter of this thesis is dedicated to the study of Hereditary Spastic Paraplegia (HSP) which is caused by mutations in neuronal kinesin-1. HSP is a disease that is thought to be caused by slowed intracellular transport by mutated kinesin-1. Two mutations, namely N256S and R280C, were experimentally shown to decrease kinesin's velocity as well as its processivity. We used structure-based Molecular Dynamic simulations to show that these mutations can lead to increased probability of open state of ATP-binding pocket of kinesin, which in its turn can lead to low velocity due to poor catalysis. We also show that in the case of N256S mutation this effect is caused by disruption of interactions between α-helix and switch I and loop L11 of kinesin.","abstract_has_math":false,"creators":["Misiura, Nikita"],"institution":"Rice University","degree_name":"Doctor of Philosophy","degree_level":"Doctoral","degree_discipline":"Natural Sciences","degree_department":null,"school":null,"contributors":[],"advisors":["Kolomeisky, Anatoly B."],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-04-23","date_published":"2020-04-23","updated_at":"2026-07-24T04:10:24Z","subjects":["ERK2","kinesin-1","IDP","Intrinsically Disordered Proteins"],"languages":["eng"],"rights":["Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1911/108400","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Kolomeisky, Anatoly B."]},{"key":"dc:creator","label":"Author","values":["Misiura, Nikita"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2020-04-27T19:22:43Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2020-04-27T19:22:43Z"]},{"key":"dc:date.issued","label":"Date","values":["2020-04-23"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Natural Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Rice University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["ERK2","kinesin-1","IDP","Intrinsically Disordered Proteins"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1911/108400"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Proteins are known to play major roles in most processes taking place inside living cells. Understanding their functions and mechanisms of their action is one of the most important problems in the fields of biochemistry and biophysics. In this work we study a kinase called Extracellular Signal Regulated Kinase 2 (ERK2), which regulates cell cell growth, adhesion, survival and differentiation, and motor protein kinesin-1. First part of this thesis is devoted to a study of ERK2-EtsΔ138 system using variety of techniques from theoretical methods, e.g. First Passage Processes method, to Molecular Dynamics and Brownian Dynamics simulations. We first gain insights into the structure of the ERK2-EtsΔ138 complex. We find that in the lowest energy complex F120 residue of EtsΔ138 occupies ψ2 hydrophobic pocket of the FRS of ERK2 and that helix H0 of EtsΔ138 is destabilized by interaction with ERK2. We then show that in the ERK2 regulation network simultaneous decrease of strengths of all interactions can lead to both decrease or increase of overall activity of ERK2 and therefore there is an optimal strength of interactions that maximizes activity. We then formulate hypothesis that one of the binding sites of ERK2 serves to accelerate protein-protein association. We use theoretical methods and simulations to show that additional binding site can accelerate association of ERK2 and EtsΔ138 by a factors from 3 to 4. The last chapter of this thesis is dedicated to the study of Hereditary Spastic Paraplegia (HSP) which is caused by mutations in neuronal kinesin-1. HSP is a disease that is thought to be caused by slowed intracellular transport by mutated kinesin-1. Two mutations, namely N256S and R280C, were experimentally shown to decrease kinesin's velocity as well as its processivity. We used structure-based Molecular Dynamic simulations to show that these mutations can lead to increased probability of open state of ATP-binding pocket of kinesin, which in its turn can lead to low velocity due to poor catalysis. We also show that in the case of N256S mutation this effect is caused by disruption of interactions between α-helix and switch I and loop L11 of kinesin."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Theoretical Studies of Protein-Protein Interactions"]}]}],"canonical_facts":{"dc:contributor.advisor":["Kolomeisky, Anatoly B."],"dc:creator":["Misiura, Nikita"],"dc:date.accessioned":["2020-04-27T19:22:43Z"],"dc:date.available":["2020-04-27T19:22:43Z"],"dc:date.issued":["2020-04-23"],"dc:description.abstract":["Proteins are known to play major roles in most processes taking place inside living cells. Understanding their functions and mechanisms of their action is one of the most important problems in the fields of biochemistry and biophysics. In this work we study a kinase called Extracellular Signal Regulated Kinase 2 (ERK2), which regulates cell cell growth, adhesion, survival and differentiation, and motor protein kinesin-1. First part of this thesis is devoted to a study of ERK2-EtsΔ138 system using variety of techniques from theoretical methods, e.g. First Passage Processes method, to Molecular Dynamics and Brownian Dynamics simulations. We first gain insights into the structure of the ERK2-EtsΔ138 complex. We find that in the lowest energy complex F120 residue of EtsΔ138 occupies ψ2 hydrophobic pocket of the FRS of ERK2 and that helix H0 of EtsΔ138 is destabilized by interaction with ERK2. We then show that in the ERK2 regulation network simultaneous decrease of strengths of all interactions can lead to both decrease or increase of overall activity of ERK2 and therefore there is an optimal strength of interactions that maximizes activity. We then formulate hypothesis that one of the binding sites of ERK2 serves to accelerate protein-protein association. We use theoretical methods and simulations to show that additional binding site can accelerate association of ERK2 and EtsΔ138 by a factors from 3 to 4. The last chapter of this thesis is dedicated to the study of Hereditary Spastic Paraplegia (HSP) which is caused by mutations in neuronal kinesin-1. HSP is a disease that is thought to be caused by slowed intracellular transport by mutated kinesin-1. Two mutations, namely N256S and R280C, were experimentally shown to decrease kinesin's velocity as well as its processivity. We used structure-based Molecular Dynamic simulations to show that these mutations can lead to increased probability of open state of ATP-binding pocket of kinesin, which in its turn can lead to low velocity due to poor catalysis. We also show that in the case of N256S mutation this effect is caused by disruption of interactions between α-helix and switch I and loop L11 of kinesin."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/1911/108400"],"dc:language.iso":["eng"],"dc:rights":["Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder."],"dc:subject":["ERK2","kinesin-1","IDP","Intrinsically Disordered Proteins"],"dc:title":["Theoretical Studies of Protein-Protein Interactions"],"dc:type":["Thesis"],"thesis:degree_discipline":["Natural Sciences"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["Rice University"]},"updated_at":"2026-07-24T04:10:24Z"}