We elucidate the molecular mechanisms of two distinct activation strategies (autophosphorylation and TPX2-mediated activation) in human Aurora A kinase. Classic allosteric is play where either loop phosphorylation or TPX2 binding to a conserved hydrophobic groove shifts equilibrium far towards active conformation. resolve controversy about mechanism autophosphorylation by demonstrating intermolecular long-lived dimer combining X-ray crystallography with functional assays. then address...

The interconversion between inactive and active protein states, traditionally described by two static structures, is at the heart of signalling. However, how folded states interconvert largely unknown due to inability experimentally observe transition pathways. Here we explore free energy landscape bacterial response regulator NtrC combining computation nuclear magnetic resonance, discover unexpected features underlying efficient We find that functional are defined purely in kinetic not...

Molecular recognition plays a central role in biology, and protein dynamics has been acknowledged to be important this process. However, it is highly debated whether conformational changes happen before ligand binding produce binding-competent state (conformational selection) or are caused response (induced fit). Proposals for both mechanisms protein/protein have primarily based on structural arguments. the distinction between them question of probabilities going via these two opposing...

Transition-state theory has provided the theoretical framework to explain enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles conformations, unique transition states would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied nature enzymatic state phosphoryl-transfer step in adenylate kinase quantum-mechanics/molecular-mechanics calculations. We find structurally wide set energetically...

We present POPACheck, the first full-fledged model checking tool for pPDA. POPACheck provides a user-friendly probabilistic modeling language with recursion that automatically translates into pOPA. pOPA are class of pPDA can express all behaviors programs. On pOPA, solve reachability queries as well qualitative and quantitative specifications in LTL fragment POTL, logic context-free properties such pre/post-conditioning.

Transition-state (TS) theory has provided the theoretical framework to explain enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles conformations, unique TSs would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied nature enzymatic TS phosphoryl-transfer step in adenylate kinase quantum-mechanics/molecular-mechanics calculations. We find structurally wide set energetically equivalent...

Multi-agent planning under stochastic dynamics is usually formalised using decentralized (partially observable) Markov decision processes ( MDPs) and reachability or expected reward specifications. In this paper, we propose a different approach: use an MDP describing how single agent operates in environment probabilistic hyperproperties to capture desired temporal objectives for set of agents operating the environment. We extend existing approaches model checking handle formulae relating...

Abstract Summary: The PiSQRD web resource can be used to subdivide protein structures in quasi-rigid dynamical domains. latter are groups of amino acids behaving as approximately rigid units the course equilibrium fluctuations. server takes input a biomolecular structure and desired fraction internal fluctuations that must accounted for by relative rigid-body motion Next, lowest energy modes fluctuation (optionally provided user) calculated identify subunits. resulting optimal subdivision is...

The near-native free energy landscape of protein G is investigated through 0.4 microseconds-long atomistic molecular dynamics simulations in explicit solvent. A theoretical and computational framework used to assess the time-dependence salient thermodynamical features. While quasi-harmonic character found degrade a few ns, slow modes display very mild dependence on trajectory duration. This property originates from striking self-similarity embodied by consistency principal directions local...

The ALADYN web server aligns pairs of protein structures by comparing their internal dynamics and detecting regions that sustain similar large-scale movements. latter often accompany functional conformational changes in proteins enzymes. dynamics-based alignment can therefore highlight functionally-oriented correspondences could be more elusive to sequence- or structure-based comparisons. takes the structure files two as input. optimal relative positioning molecules is found maximizing...

Proteins and enzymes, in order to carry our their biological tasks, often need sustain concerted displacements of a large number amino acids. In recent years many theoretical computational studies have pointed out how these large-scale movements, also termed slow modes or essential dynamical spaces, are mostly dictated by the overall structural organization protein. Several fundamental questions arise when this fact is complemented observation that enzymes within same enzymatic superfamily...

Low energy modes have been calculated for the largest possible number of available representatives (>150) EF-hand domains belonging to different members calcium-binding protein superfamily. These proteins are major actors in signal transduction. The latter, turn, relies on dynamical properties systems, particular relative movements four helices characterizing each domain upon calcium binding. peculiar structural and features this superfamily systematically investigated by a novel approach,...

The problem of extending model checking from finite state machines to procedural programs has fostered much research toward the definition temporal logics for reasoning on context-free structures. most notable such results are Nested Words, as CaRet and NWTL. Recently, Precedence Oriented Temporal Logic (POTL) been introduced specify prove properties coded trough an Operator Language (OPL). POTL is complete w.r.t. FO restriction MSO logic previously defined a fully equivalent OPL. increases...

Abstract Transition-state theory has provided the theoretical framework to explain enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles conformations, unique transition states would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied nature enzymatic state phosphoryl-transfer step in adenylate kinase quantum-mechanics/molecular-mechanics calculations. We find structurally wide set energetically...

We address the problem of model checking temporal logic specifications for probabilistic programs with recursive procedures, nested queries, and conditioning expressed observe statements. introduce Operator Precedence Automata (pOPA), a new class pushdown automata suitable to constructs behaviors programs. develop algorithm that can verify requirements in fragment Oriented Temporal Logic (POTL$^f_\mathcal{X}$) on pOPA single EXPTIME. POTL$^f_\mathcal{X}$ is based Languages, which features...

Transition-state theory has provided the theoretical framework to explain enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles conformations, unique transition states would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied nature enzymatic state phosphoryl-transfer step in adenylate kinase quantum-mechanics/molecular-mechanics calculations. We find structurally wide set energetically...