National Energy Research Scientific Computing Center (NERSC) NERSC 2022 Early Career Achievement Award Seminars, 19 Dec 2022

Previous Meeting

Next Meeting

⏯

youtube image

►

From YouTube: Giulia Palermo: Dynamics and mechanisms of CRISPR-Cas9 through the lens of computational methods

Description

Dynamics and mechanisms of CRISPR-Cas9 through the lens of computational methods
Giulia Palermo, University of California, Riverside

December 13, 2022

11:00-11:30 Pacific Time

The clustered regularly interspaced short palindromic repeat (CRISPR) genome-editing revolution established the beginning of a new era in life sciences. I will report the role of state-of-the-art computations in the CRISPR-Cas9 revolution, from the early refinement of cryo-EM data to enhanced simulations of large-scale conformational transitions. Molecular simulations reported a mechanism for RNA binding and the formation of a catalytically competent Cas9 enzyme, in agreement with subsequent structural studies. Inspired by single-molecule experiments, molecular dynamics offered a rationale for the onset of off-target effects, while graph theory unveiled the allosteric regulation. Finally, the use of a mixed quantum-classical approach established the catalytic mecha- nism of DNA cleavage. Overall, molecular simulations have been instrumental in understanding the dynamics and mech- anism of CRISPR-Cas9, contributing to understanding func- tion, catalysis, allostery, and specificity.

A

Abatte al System deviros in Jacks Home, genetic Material Witch gets and Bed Into the bacterial genoveses a protein cast Nine Which byins, again arenai witchesable to recruit di Nissan almerald for doubles su. We have been interested in character, Rising asseries of biofisical Open questions, We like to say that cast Nine di spruting work, satellite Silk Artist that first Bynes di arenei changes conformation to grab DNA e macht.

A

Su we have been interested in character, Rising discomformational changes, di allosterix, Response di aftarget, Effects and cleved mechanis.

A

Any fancides of minima Death corresponded to di crystal structure and cryorstruction Ready Present Battles of forth minimal, with We propose the to be a piùtative Active States doct, a The cleavageside to perform cleavages. So This is States actalicum structure, All Days about it batacapolo via arcelater, Afterhours, Afterhours, Paper, to structures.

A

Computation sowing that we have, I similarity with of cryo y mstrakture di dynamics. Ovation Age is very important for the Empire function of the crispr Cast Nine System In fact: It was hypothesize in The Leader ACR, that di comfo Around Change Wood, activate analostery cresponsive System by Witch eichnation rap Seat, Talk, wittytchader allosterica there, after the binding of a Recognition sequence, located distal with you, Spectrum Star Ted from desisa hypotheses Present in the literature and he investigates and Dj hypotheses True molecular simulations network Models.

A

The right fromgraph Theory with this metles weekend describes the protein is a set of knows and edges. Where It's not is an aminoacid Each Edge is wated by correlations. Sono Stronger, the correlation The closer. The knows, and we can proses This is correlations. Culture.

A

E spassing perché non so use algorithm algorithms to calculate the short. A statuto is from One Side, for example, di acenage, cataliticside To, the rap Sea catalytic side computing, the short test pathways from hei ght to see Forex sample disinvestigations performing molecular simulations Park ninebound to Pam and di absenz of Pam.

A

This short recognitions, è tuo supposto, activate di allosterism between eichnation by accomplishing correlation Destruction of the correlations in the System We, founded in the presents of Pam correlations between and cenated Wild hubsense of Pump discaple motions, Get, basically Broken sagesting, That, chiocciole atipica al Sign o va allosterica effector Anna, lo steriche factorys scaracter Eyes by the funkt that di dynamics of the System is completely shifted and This is, after the binding to dance structure, di allosterix signaling, showing that di Communication between Nation Rav, Secret, stranded, In, The, Presence of Pam and does a identify.

A

What is ajust to be the main allosteric Ruth of Communication between the to catalytic Domain, witchwas, farther supported by experimental datay identity. This one's identity, Pam activates di dynamics, ovation rap Sea, Witt y Side to capolavor work with anymore and partner, University George.

A

Transmission Giorgia è identityus, with Wear Shawn to be Slow truce, PNG entered di Digital algorithm We ha identity, connecting Recognition Region di enere, con glition Region with the DNA cleavage Size e lui Found. This patways di patways of the anymore and paths of talentwood Digital algorithm, Where, superposable, sagesting, gli enti, finding root connecting the Psycho Recognition to the site of cleved.

A

What is the Communication Game and the Communication Loss apon mutation here in displot You can see acenage color We different colors that character Eyes Community is Ovest that Ice by high syncronic dynamics and discom units, where the Find a allosteric e nota, lo steric, dialosterico Community, is the one that transfer di stato, posto un from del Recognition site to the cleverad side and the one that host di Slow recessidios Found with anymar the one that transfer of information by Adel Community y Isar.

A

Clearly community is there le strelevant for di transmissions Theory with computer, the Communication Game and Loss apon di skinmutations observing di allosteric communityes Communication, a pon mutation show in the dressdious Pam per basically break the main Communication pub.

A

Di computational investigations with anymore yesterday in diplots You, can see by communityes dynamics, WeChat computers or cams From computations. This Bones dei come from anymar su This is by experimental Dynamic Exchange between Community sticker by experimental Dynamic exchanges. Hair is ob-serving in the wild Type and you and the mutation Is Present by Dynamic Exchange Get highly the greased In The Presence of the motion with Father con farms said specie chi si tiene ancement of this mutants is links.

A

Allosteric signaling.

A

Communication Present in cast Nine and dolce post. The bases to karacter is how Mule develop Variant Italia's work and if the Day Alter of allosterism in the System, hesitant sagested by single monaghtur Experiments.

A

Target Trend the one thatches non target: Trend Trudy, AID of Metal iOS magnesium iOS in this case to karacter, is the mechanism of the nakeverage wiperford Quantum meccanics. Molecular mechanics simulations in this case of active-city Street, a ta Quantum mechanical level of the story using dancity, functional Theory, Wild rest of the System itad to classical mechanics and the dynamics of the System was propagated in discape. By using a carparinello approach, introduces Electronics tu, Speed up di dynamics of corso di simulations of very expensive.

A

We have to Temple very much to get converge, crea Energy profiles and di Basic Slow and require massive computational resources. Su We start di investigate, investigating sight, Where, To, Catherine, Metal saar supposed toccata life in this case.

A

In the Early crystallographic tractures upstream During, the simulations prefared to As You A Down conformation binding tight tly Foster, which in habel SAS to sa Jazz good.

A

Energy profile using a Benicio omelette, Lord dynamics, Enter modem integrations simulation sagested, the catalisis of Core True, atypical Essence. To me mechanism, Where This is Basic. A little chiactor in activating catalesis was conference Experiments by janischantus Barkley e dolson. Our barrier was in Line with di observed Cake at di observed rate for the rapsido main most important Destruction of decatalytic magnesium bound rap seactive, Sound 21 Farming awarubservations.

A

In particular. The Funk disagi in Points toward di shissell foste, been to stabilad sister Foster and the Easter in the Twist propose to be the acting catalysis, pointed toward di Active Sides of the truth. Simulator.

A

Where di configuration of the Active sidesnot complete Clear.

A

Study of the catalysis of the other catalyticside, in this case di investigations Complicated. The reason whyure Complicated is because several Crystal trackers.

A

Sajusted to with figuration of the catalyticside Where To was party kasses pointed toward manisium disasteroctures.

A

A

With a simila nuclear Endo, Seven People tallt that.

A

Point toward magnesium and basicaride catalisis good happening disco configuration batmosteries, ently, New, Cry, amstracture.

A

Free Energy simulations umbrella, semping with and without magnesium. This simulation Proust, the tweet magnesium di Active configurations of the newly reporterstruction was prefer Welling di absonce of magnesium. The pseudo Active su.

A

System to be Active, Ford, clearfort, thermodinamica integration on the too Systems di Active and seedo acting observing Dead barrier for the catanist is much Lower. Then the Active state, denning Active state and the reason Why so Low is Because in the Active state di polarization of magnesium e Such to live di autry prime witches The Living group mornegative innails of The Living group with respect To, The, Future, Active States prime, is much more p.

A

Ositive and Hands Living Group di transition, state Energy, weautoperford, meta dynamics to Father conferm di smeccanistments, Free, Energy approach, thetables to character, Eyes, the machines My going Back My, going back and forth a long di collective variables in discapes, a Movie I think is better up. Ited to Show house, catalytic mechanismo, or course here. You can see first wolver introducing System isaceli, a very large System and it Wars System seamulet.

A

Fior dynamics, the large System Simulator.

A

Hybrid System e I geneichwood get activated on wewonder Why This is happening on We perform accelerated, molecular Dynamic simulation of Chris Brothers Nine, including bestemmings.

A

Of Nature there extended opening of the hybrids to Strong interactions, WeChat di minishin di Mobility.

A

Ovational activation su This is observations: di opening of the Hybrid obserrd Wiki xray Crystal lografi by Martin ginek Who conford Disar li observations that simulations fecirter inspire doe s to useon Dynamic simulations to predict.

A

Lab finally, This is Movie of Target interactions: La locking eichnach When in Present of matches. Yesterday You can see Audi of target interactions. Of course.

A

A

Simulations weekend news, gpuse, in-law, gpu user, veri e fishement, Today tourant, classical molecular Dynamic simulations.

A

Hybrid mixed Quantum, classical simulations Winnie to the Lions sipus and di traditionally Extreme expensive simulations Now. This a New code, That.

A

A