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    <journal-meta>
      <journal-id journal-id-type="nlm-ta">reapress</journal-id>
      <journal-id journal-id-type="publisher-id">null</journal-id>
      <journal-title>reapress</journal-title><issn pub-type="ppub">3042-2248</issn><issn pub-type="epub">3042-2248</issn><publisher>
      	<publisher-name>reapress</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="doi">https://doi.org/10.48313/maa.v3i3.115 </article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Research Article</subject>
        </subj-group>
        <subj-group><subject>Protein conformational search, Swarm intelligence, Energy landscape minimization, CASP benchmarks, Hybrid metaheuristics, Graph neural network surrogates.</subject></subj-group>
      </article-categories>
      <title-group>
        <article-title>Population-Based Search for Conformational Energy Minimization in Protein Folding: A Critical Synthesis of Swarm, Evolutionary and Hybrid Schemes (2000–2026)</article-title><subtitle>Population-Based Search for Conformational Energy Minimization in Protein Folding: A Critical Synthesis of Swarm, Evolutionary and Hybrid Schemes (2000–2026)</subtitle></title-group>
      <contrib-group><contrib contrib-type="author">
	<name name-style="western">
	<surname>Vázquez</surname>
		<given-names>Elena M. </given-names>
	</name>
	<aff>Madrid Institute for Advanced Studies in Computational Biology (IMDEA-Food), 28012 Madrid, Spain.</aff>
	</contrib><contrib contrib-type="author">
	<name name-style="western">
	<surname> Subramanian</surname>
		<given-names>Ravi</given-names>
	</name>
	<aff>Indian Institute of Science (IISc), Department of Computational & Data Sciences, Bengaluru 560012, India.</aff>
	</contrib><contrib contrib-type="author">
	<name name-style="western">
	<surname> Nowak</surname>
		<given-names>Katarzyna M.</given-names>
	</name>
	<aff>University of Warsaw, Centre for Theoretical Chemistry, 02-093 Warszawa, Poland.</aff>
	</contrib><contrib contrib-type="author">
	<name name-style="western">
	<surname>Mensah</surname>
		<given-names>Aisha K. </given-names>
	</name>
	<aff>University of Cape Town, Computational Biology Division, IDM, Cape Town 7925, South Africa.</aff>
	</contrib></contrib-group>		
      <pub-date pub-type="ppub">
        <month>09</month>
        <year>2026</year>
      </pub-date>
      <pub-date pub-type="epub">
        <day>07</day>
        <month>09</month>
        <year>2026</year>
      </pub-date>
      <volume>3</volume>
      <issue>3</issue>
      <permissions>
        <copyright-statement>© 2026 reapress</copyright-statement>
        <copyright-year>2026</copyright-year>
        <license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license>
      </permissions>
      <related-article related-article-type="companion" vol="2" page="e235" id="RA1" ext-link-type="pmc">
			<article-title>Population-Based Search for Conformational Energy Minimization in Protein Folding: A Critical Synthesis of Swarm, Evolutionary and Hybrid Schemes (2000–2026)</article-title>
      </related-article>
	  <abstract abstract-type="toc">
		<p>
			The protein-folding problem has undergone three paradigm shifts in the past quarter-century: The consolidation of population-based metaheuristics as the dominant pre-2018 workhorse, the deep-learning disruption of AlphaFold2 and RoseTTAFold in mid-2021, and the ongoing post-AlphaFold synthesis in which swarm, evolutionary, and hybrid schemes find renewed roles in refinement, Intrinsically Disordered Proteins (IDPs), multimer assembly, and free-energy perturbation along reaction coordinates. This critical survey covers 2000–2026 and proposes a four-level taxonomy classifying methods along: 1) search-space representation (lattice, torsion-angle, Cartesian all-atom, coarse-grained), 2) energy model (Go-type, Rosetta ref2015, AMBER/CHARMM, ML-surrogate), 3) operator family (Particle Swarm Optimisation (PSO), Ant Colony Optimisation (ACO), Genetic Algorithms (GAs)/Differential Evolution (DE)/CMA-ES/Estimation of Distribution Algorithms (EDA), Basin-Hopping (BH)/Replica-Exchange Monte Carlo (REMC)), and 4) hybridisation pattern (sequential, interleaved, surrogate-assisted, decomposition). We reanalyse published results on five benchmark families (the HP-lattice FCC Dill set, Rosetta ab initio, CASP13-15 targets across TBM/FM/Refinement/Multimer classes, PDB-redo refinement, and MARTINI coarse-grained complexes) under a common evaluation budget of 100 000 energy evaluations. The statistical protocol comprises the Friedman test (χ² = 89.4, df = 11, p < 0.001), Nemenyi post-hoc analysis (CD = 1.18 at α = 0.05), pairwise Wilcoxon signed-rank tests with Holm-Bonferroni (and Bonferroni secondary) correction, Cliff's δ and Vargha-Delaney A₁₂ effect sizes, 1000-resample bootstrap 95% CIs, post-hoc achieved power, and TOST equivalence testing. Top-ranked methods are hybrid memetic schemes (PSO + Rosetta relax; DE + fragment assembly), with pure swarm methods retaining an edge on lattice benchmarks. Graph-Neural-Network (GNN) surrogates achieve comparable RMSD at three-fold reduced wall-clock. We close with a prioritised five-challenge roadmap covering Noisy Intermediate-Scale Quantum (NISQ) quantum-classical hybrids, adaptive operator selection via Upper-Confidence-Bound (UCB) bandits, and reproducibility artefacts that respond directly to the AlphaFold-era data-shift.
		</p>
		</abstract>
    </article-meta>
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